pmid title sentence year journal region virus mutation mutation_start mutation_end gene gene_start gene_end disease disease_start disease_end 9813214 Rescue of the Epstein-Barr virus BZLF1 mutant, Z(S186A), early gene activation defect by the BRLF1 gene product. Rescue of the Epstein-Barr virus BZLF1 mutant, Z(S186A), early gene activation defect by the BRLF1 gene product. 1998 Virology Title EBV S186A 49 54 BRLF1;BZLF1;BZLF1 93;33;47 98;38;48 10209951 Sequence polymorphisms between latent membrane proteins LMP1 and LMP2A do not correlate in EBV-associated reactive and malignant lympho-proliferations. The B95.8 prototype was found in 17% (13/76) of cases, while in 72% a variant with 3 point mutations (166796 C-->A, 166805 C-->A, 166810 C-->T) was detected; 11% had 1 or 2 of these mutations in addition to G-->A at 166793. 1999 International journal of cancer Abstract EBV C166796A;C166805A;C166810T;G166793A 102;116;130;207 114;128;142;222 10209951 Sequence polymorphisms between latent membrane proteins LMP1 and LMP2A do not correlate in EBV-associated reactive and malignant lympho-proliferations. The CTL motif was conserved in all but 2 cases (C426-->S). 1999 International journal of cancer Abstract EBV C426S 48 56 10233912 Amino acid substitutions reveal distinct functions of serine 186 of the ZEBRA protein in activation of early lytic cycle genes and synergy with the Epstein-Barr virus R transactivator. A second class, represented by Z(S186C) and Z(S186G), was impaired in transcriptional activation, unable to activate early lytic cycle products from the latent virus, and not rescued by overexpression of Rta. 1999 Journal of virology Abstract EBV S186C;S186G 33;46 38;51 BRLF1;BZLF1;BZLF1 204;31;44 207;32;45 10233912 Amino acid substitutions reveal distinct functions of serine 186 of the ZEBRA protein in activation of early lytic cycle genes and synergy with the Epstein-Barr virus R transactivator. A third class, Z(S186A), although unable by itself to activate BRLF1 or other lytic cycle genes, synergized with Rta. 1999 Journal of virology Abstract EBV S186A 17 22 BRLF1;BRLF1;BZLF1 63;113;15 68;116;16 10233912 Amino acid substitutions reveal distinct functions of serine 186 of the ZEBRA protein in activation of early lytic cycle genes and synergy with the Epstein-Barr virus R transactivator. However, since Z(S186A) could synergize with Rta, synergy with Rta does not appear to be dependent on phosphorylation of S186. 1999 Journal of virology Abstract EBV S186A 17 22 BRLF1;BRLF1;BZLF1 45;63;15 48;66;16 10233912 Amino acid substitutions reveal distinct functions of serine 186 of the ZEBRA protein in activation of early lytic cycle genes and synergy with the Epstein-Barr virus R transactivator. One mutant class, represented by Z(S186T), was similar to the wild type, although reduced in the capacity to activate BRLF1 and BMRF1 early lytic cycle genes from the latent virus. 1999 Journal of virology Abstract EBV S186T 35 40 BMRF1;BRLF1;BZLF1 128;118;33 133;123;34 10233912 Amino acid substitutions reveal distinct functions of serine 186 of the ZEBRA protein in activation of early lytic cycle genes and synergy with the Epstein-Barr virus R transactivator. Rta rescued the capacity of Z(S186A) to activate the BMRF1 early lytic cycle gene from the latent virus. 1999 Journal of virology Abstract EBV S186A 30 35 BMRF1;BRLF1;BZLF1 53;0;28 58;3;29 10233912 Amino acid substitutions reveal distinct functions of serine 186 of the ZEBRA protein in activation of early lytic cycle genes and synergy with the Epstein-Barr virus R transactivator. Since only Z(S186T) among the mutants behaved similarly to the wild type, activation of BRLF1 likely requires phosphorylation of S186. 1999 Journal of virology Abstract EBV S186T 13 18 BRLF1;BZLF1 88;11 93;12 10233912 Amino acid substitutions reveal distinct functions of serine 186 of the ZEBRA protein in activation of early lytic cycle genes and synergy with the Epstein-Barr virus R transactivator. Z(S186A), a point mutant in ZEBRA's basic domain in which serine 186 is changed to alanine, is unable to induce expression of lytic cycle mRNAs or proteins from the latent EBV genome even though it retains the ability to activate transcription from reporters bearing known ZEBRA-responsive promoters (A. 1999 Journal of virology Abstract EBV S186A;S186A 1;58 7;90 BZLF1;BZLF1;BZLF1 0;28;273 1;33;278 10381519 EBNA-1 gene sequences in Brazilian and American patients with Hodgkin's disease. Compared with the P-ala and P-thr cases, the V-leu cases were more likely to have the 30-bp latent membrane protein 1 (LMP1) gene deletion (P = 0.0075). 1999 Blood Abstract EBV del 30-bp 86 91 LMP1;LMP1 92;119 117;123 10381519 EBNA-1 gene sequences in Brazilian and American patients with Hodgkin's disease. In addition, cases of HD with the V-leu were statistically associated with a substitution of asparagine for glutamine at codon 322 of the C-terminal portion of the LMP1 gene. 1999 Blood Abstract EBV Q322N 93 130 LMP1 164 168 Hodgkin disease 22 24 10559298 Role of the epstein-barr virus RTA protein in activation of distinct classes of viral lytic cycle genes. The use of the Z(S186A) mutant form of ZEBRA, whose transactivation function is manifest only by coexpression of Rta, allows identification of a second class of lytic cycle genes, such as BMRF1 and BHRF1, that are activated in synergy by Rta and ZEBRA. 1999 Journal of virology Abstract EBV S186A 17 22 BHRF1;BMRF1;BZLF1;BZLF1;BRLF1;BRLF1;BZLF1 198;188;39;246;113;238;15 203;193;44;251;116;241;16 11432667 Differences in EBNA2 and LMP-1 carboxy terminal region sequences of Epstein-Barr virus type A between the tumors in a multiple cancer patient. Although the squamous cell carcinoma of the tongue occurred after an interval of 18 years, the mutation site in the carcinomas was the same, 49137 (A-->G), as compared with B95-8 strain EBV EBNA2. 2001 Pathology, research and practice Abstract EBV A49137G 141 154 EBNA2 190 195 Squamous cell carcinoma of head and neck 13 50 11432667 Differences in EBNA2 and LMP-1 carboxy terminal region sequences of Epstein-Barr virus type A between the tumors in a multiple cancer patient. The mutations at 48991 (G-->T) and 48998 (C-->A) were demonstrated in the lymphoma. 2001 Pathology, research and practice Abstract EBV G48991T;C48998A 17;35 30;48 Lymphoma 74 82 11783104 [Increase of EGFR expression by Epstein-Barr virus LMP1 in nasopharyngeal carcinoma cells]. METHODS: Stable transfectant HNE2 cell line expressing LMP1 (HNE2-LMP1) or its mutants (HNE2 del 187-351, HNE2 1-231, HNE2 1-187) were used as cell models. 2001 Zhonghua zhong liu za zhi [Chinese journal of oncology] Abstract EBV del 187-351;del 1-231;del 1-187 93;111;123 104;116;128 LMP1;LMP1 55;66 59;70 12037022 Epstein-Barr virus (EBV) subtype in EBV related oral squamous cell carcinoma in Okinawa, a subtropical island in southern Japan, compared with Kitakyushu and Kumamoto in mainland Japan. Sequence analysis of the type A virus EBNA2 gene revealed slight variations of the sequence (mutations)-(48991)G-->T and (48998)C-->A-in 18 of 33 cases compared with the B95-8 strain, and in 14 cases, in addition to these, a further mutation of (48917)T-->C was demonstrated; in the single remaining case, only one mutation at (49137)A-->G was detected. 2002 Journal of clinical pathology Abstract EBV T48917C;A49137G 245;327 257;339 EBNA2 38 43 12037022 Epstein-Barr virus (EBV) subtype in EBV related oral squamous cell carcinoma in Okinawa, a subtropical island in southern Japan, compared with Kitakyushu and Kumamoto in mainland Japan. The (48991)G-->T and (48998)C-->A mutations of the EBNA2 region were demonstrated in type A virus, but the (48917)T-->C and (49137)A-->G mutations were not when compared with the B95-8 strain. 2002 Journal of clinical pathology Abstract EBV T48917C;A49137G 107;124 119;136 EBNA2 51 56 12037022 Epstein-Barr virus (EBV) subtype in EBV related oral squamous cell carcinoma in Okinawa, a subtropical island in southern Japan, compared with Kitakyushu and Kumamoto in mainland Japan. The mutations at 48991 (G-->T), and 49137 (A-->G) are associated with amino acid changes Arg-->Met and Thr-->Ala, respectively. 2002 Journal of clinical pathology Abstract EBV G48991T;A49137G 17;36 30;49 12388679 Disruption of Epstein-Barr virus latency in the absence of phosphorylation of ZEBRA by protein kinase C. Of greatest importance, in vivo labeling with [(32)P]orthophosphate showed that the tryptic phosphopeptide maps of wild-type ZEBRA, Z(S186A), and the double mutant Z(T159A/S186A) were identical. 2002 Journal of virology Abstract EBV S186A;T159A;S186A 134;166;172 139;171;177 BZLF1;BZLF1;BZLF1 132;164;125 133;165;130 12388679 Disruption of Epstein-Barr virus latency in the absence of phosphorylation of ZEBRA by protein kinase C. Studies in cell culture showed that phosphorylation of T159 was not required for disruption of latency in vivo, since the T159A mutant was fully functional. 2002 Journal of virology Abstract EBV T159A 122 127 12604820 Site-directed mutagenesis in a conserved motif of Epstein-Barr virus DNase that is homologous to the catalytic centre of type II restriction endonucleases. Biochemical analysis indicated that the preference for divalent cations was altered from Mg2+ to Mn2+ for mutant E225D. 2003 The Journal of general virology Abstract EBV E225D 113 118 12604820 Site-directed mutagenesis in a conserved motif of Epstein-Barr virus DNase that is homologous to the catalytic centre of type II restriction endonucleases. Five of these six variants retained nuclease activity and mutant D195N alone lost nuclease activity. 2003 The Journal of general virology Abstract EBV D195N 65 70 12604820 Site-directed mutagenesis in a conserved motif of Epstein-Barr virus DNase that is homologous to the catalytic centre of type II restriction endonucleases. However, K227 mutants were found to have variable DNA-binding abilities: K227G and K227N mutants retained, K227E and K227D had reduced and K227R lost DNA-binding ability. 2003 The Journal of general virology Abstract EBV K227G;K227N;K227E;K227D;K227R 73;83;107;117;139 78;88;112;122;144 12604820 Site-directed mutagenesis in a conserved motif of Epstein-Barr virus DNase that is homologous to the catalytic centre of type II restriction endonucleases. The DNA-binding abilities of D203E, E225D and E225Q were shown to be similar to that of wild-type. 2003 The Journal of general virology Abstract EBV D203E;E225D;E225Q 29;36;46 34;41;51 14705959 Identification and characterization of the conserved nucleoside-binding sites in the Epstein-Barr virus thymidine kinase. For site 3, only mutants D392E (Asp392-->Glu) and R393H retain activity, indicating that a negative charge is important for Asp392 and a positive charge is required for Arg393. 2004 The Biochemical journal Abstract EBV D392E;R393H;D392E 25;50;32 30;55;44 14705959 Identification and characterization of the conserved nucleoside-binding sites in the Epstein-Barr virus thymidine kinase. In site 4, the F402Y mutant retains full activity; however, F402S retains only 60% relative activity. 2004 The Biochemical journal Abstract EBV F402Y;F402S 15;60 20;65 14705959 Identification and characterization of the conserved nucleoside-binding sites in the Epstein-Barr virus thymidine kinase. Interestingly, the changed metal-ion usage pattern of D392E reveals that Asp392 plays multiple roles in this region. 2004 The Biochemical journal Abstract EBV D392E 54 59 14705959 Identification and characterization of the conserved nucleoside-binding sites in the Epstein-Barr virus thymidine kinase. Strikingly, when Phe402 is substituted with serine residue, the original preferred pyrimidine substrates, such as 3'-azido-3'-deoxythymidine, iododeoxyuridine and beta-L-5-iododioxolane uracil (L-form substrate), have decreased competitiveness with thymidine, suggesting that Phe402 plays a crucial role in substrate specificity and that the aromatic ring is important for function. 2004 The Biochemical journal Abstract EBV F402S 17 50 15215688 BAMHI DNA fragment H-polymorphism of Epstein-Barr virus is associated with the mutations present in an 89 BP sequence localized in EBNA2 gene. By nucleotide sequence analysis, we showed that there were two specific missense mutations in an 89 bp region of EBNA2 gene at position 49390-49479 of the EBV genome: a mutation at 49449 (C-->A) and another mutation at 49444 (T-->C), changing their amino acid sequence. 2004 Virus genes Abstract EBV C49449A;T49444C 181;219 194;232 EBNA2 113 118 15779905 Characterization of three essential residues in the conserved ATP-binding region of Epstein-Barr virus thymidine kinase. As the enzyme activity of G294A was reduced to 20% of that of wtTK, the K(m) for ATP binding of G294A was 48.7 microM as compared with 30.0 microM of EBV wtTK. 2005 Biochemistry Abstract EBV G294A;G294A 26;96 31;101 TK;TK 64;156 68;160 15779905 Characterization of three essential residues in the conserved ATP-binding region of Epstein-Barr virus thymidine kinase. EBV TK mutants K297E, K297Q, and K297R lost their ATP-binding ability and enzyme activity. 2005 Biochemistry Abstract EBV K297E;K297Q;K297R 15;22;33 20;27;38 TK 4 6 15779905 Characterization of three essential residues in the conserved ATP-binding region of Epstein-Barr virus thymidine kinase. However, K297R was shown to have a preference for usage of GTP (K(m): 43.0 microM) instead of ATP (K(m): 87.6 microM) as the phosphate donor. 2005 Biochemistry Abstract EBV K297R 9 14 15779905 Characterization of three essential residues in the conserved ATP-binding region of Epstein-Barr virus thymidine kinase. Interestingly, T298A retained its ATP-binding ability, suggesting a role of T298 in the catalytic process but not in the coordination of ATP. 2005 Biochemistry Abstract EBV T298A 15 20 15779905 Characterization of three essential residues in the conserved ATP-binding region of Epstein-Barr virus thymidine kinase. Mutant G294V lost its ATP-binding ability and was inactive in enzyme activity assay. 2005 Biochemistry Abstract EBV G294V 7 12 15779905 Characterization of three essential residues in the conserved ATP-binding region of Epstein-Barr virus thymidine kinase. While EBV TK mutant T298S retained approximately 80% of wtTK enzyme activity, T298A lost its enzyme activity, suggesting that a hydroxyl group at this position is important for the enzyme activity. 2005 Biochemistry Abstract EBV T298S;T298A 20;78 25;83 TK;TK 58;10 62;12 15919888 BZLF1 activation of the methylated form of the BRLF1 immediate-early promoter is regulated by BZLF1 residue 186. A Z mutant containing an alanine residue at position 186 [Z(S186A)] was significantly defective in binding to methylated, as well as unmethylated, ZREs (Z-responsive elements) in Rp and was unable to activate lytic EBV gene transcription from the methylated or demethylated form of the viral genome. 2005 Journal of virology Abstract EBV S186A 60 65 BZLF1;BZLF1;BZLF1 2;58;153 3;59;154 15919888 BZLF1 activation of the methylated form of the BRLF1 immediate-early promoter is regulated by BZLF1 residue 186. A Z mutant containing threonine at residue 186 [Z(S186T)] bound only to the methylated form of the ZRE-2 site in Rp and induced lytic EBV gene transcription from the methylated, but not demethylated, form of the viral genome. 2005 Journal of virology Abstract EBV S186T 50 55 BZLF1;BZLF1 2;48 3;49 15919888 BZLF1 activation of the methylated form of the BRLF1 immediate-early promoter is regulated by BZLF1 residue 186. Finally, a Z mutant containing an aspartic acid at position 186 [Z(S186D)] did not bind to either the consensus AP-1 site or to the methylated or unmethylated Rp ZRE-2 site and did not induce lytic gene transcription. 2005 Journal of virology Abstract EBV S186D 67 72 BZLF1;BZLF1 11;65 12;66 15919888 BZLF1 activation of the methylated form of the BRLF1 immediate-early promoter is regulated by BZLF1 residue 186. These results indicate that replacement of serine with threonine at residue 186 in the Z DNA-binding domain differentially affects its ability to reactivate the unmethylated, versus methylated, viral genome. 2005 Journal of virology Abstract EBV S186T 43 79 BZLF1 87 88 16160168 The amino terminus of Epstein-Barr virus glycoprotein gH is important for fusion with epithelial and B cells. Reduction in fusion activity was observed for mutants containing L65A and/or L69A mutations, while substitutions in L55 and L74 enhanced the fusion activity of the mutant gH/gL complexes with both cell types. 2005 Journal of virology Abstract EBV L65A;L69A 65;77 69;81 gH;gL 171;174 173;176 16227252 A redox-sensitive cysteine in Zta is required for Epstein-Barr virus lytic cycle DNA replication. C189S did provide some resistance to oxidation and nitrosylation, which potently inhibit Zta DNA binding activity in vitro. 2005 Journal of virology Abstract EBV C189S 0 5 BZLF1 89 92 16227252 A redox-sensitive cysteine in Zta is required for Epstein-Barr virus lytic cycle DNA replication. C189S was deficient for transcription activation of several viral late genes that depend on lytic replication and therefore was consistent with a primary defect of C189S in activating lytic replication. 2005 Journal of virology Abstract EBV C189S;C189S 0;164 5;169 16227252 A redox-sensitive cysteine in Zta is required for Epstein-Barr virus lytic cycle DNA replication. C189S was not defective in binding methylated DNA binding sites and was capable of activating Rta from endogenous latent viral genomes, in contrast to the previously characterized S186A mutation. 2005 Journal of virology Abstract EBV C189S;S186A 0;180 5;185 BRLF1 94 97 16227252 A redox-sensitive cysteine in Zta is required for Epstein-Barr virus lytic cycle DNA replication. C189S was slightly impaired for its ability to form a stable complex with Rta, although this did not prevent Rta recruitment to OriLyt. 2005 Journal of virology Abstract EBV C189S 0 5 BRLF1;BRLF1 74;109 77;112 16227252 A redox-sensitive cysteine in Zta is required for Epstein-Barr virus lytic cycle DNA replication. In this work, we show that replacement of C189 with serine (C189S) eliminated lytic cycle DNA replication function of Zta. 2005 Journal of virology Abstract EBV C189S 60 65 BZLF1 118 121 16227252 A redox-sensitive cysteine in Zta is required for Epstein-Barr virus lytic cycle DNA replication. Interestingly, this redox sensitivity was not strictly dependent on C189S but involved additional cysteine residues in Zta. 2005 Journal of virology Abstract EBV C189S 68 73 BZLF1 119 122 16227252 A redox-sensitive cysteine in Zta is required for Epstein-Barr virus lytic cycle DNA replication. We also show that C189S was not defective for transcription activation of EBV early gene promoters. 2005 Journal of virology Abstract EBV C189S 18 23 16227252 A redox-sensitive cysteine in Zta is required for Epstein-Barr virus lytic cycle DNA replication. We show that C189S was not significantly altered for DNA binding activity in vitro or in vivo. 2005 Journal of virology Abstract EBV C189S 13 18 16406456 Regulation of the expression of the Epstein-Barr virus early gene BFRF1. However, a co-operative effect between ZEBRA and RTA in the expression of BFRF1 is evident since the transfection of RTA can rescue the transactivating capacity of a mutant of the ZEBRA protein, known as Z(S186A), that has a substitution affecting the DNA binding region. 2006 Virology Abstract EBV S186A 206 211 BFRF1;BZLF1;BZLF1;BRLF1;BRLF1;BZLF1 74;39;180;49;117;204 79;44;185;52;120;205 16917737 Sequence variations of Epstein-Barr virus LMP1 gene in nasal NK/T-cell lymphoma. In the epitopes ALLVLYSFA (codon 51-59), VLFIFGCLL (codon 110-118) and WLLLFLAIL (codon 173-181), several patients showed novel amino acid changes at codon 59 (Ala to Gly), 110 (Val to Leu) and 174 (Leu to Ile), respectively. 2007 Virus genes Abstract EBV A59G;V110L;L174I 156;173;194 171;189;210 16917737 Sequence variations of Epstein-Barr virus LMP1 gene in nasal NK/T-cell lymphoma. In the major HLA-A2 restricted T-cell epitope sequence YLLEMLWRL (codon 125-133), all 7 patients showed amino acid changes at codon 126 (Leu to Phe) and 129 (Met to Ile). 2007 Virus genes Abstract EBV L126F;M129I 132;153 148;169 16917737 Sequence variations of Epstein-Barr virus LMP1 gene in nasal NK/T-cell lymphoma. Within the NF-kB-activating domains, all 7 patients showed amino acid changes at codon 189 (Gln to Pro), 192 (Ser to Thr) and 212 (Gly to Ser) on either site of the PXQXT (codon 204-208) motif. 2007 Virus genes Abstract EBV Q189P;S192T;G212S 87;105;126 103;121;142 16940523 Amino acids in the basic domain of Epstein-Barr virus ZEBRA protein play distinct roles in DNA binding, activation of early lytic gene expression, and promotion of viral DNA replication. Mutants competent to bind DNA could be separated into four functional groups: the wild-type group (eight mutants), a group defective at activating Rta (five mutants, all with mutations at the S186 site), a group defective at activating EA-D (three mutants with the R179A, S186T, and K192A mutations), and a group specifically defective at activating late gene expression (seven mutants). 2006 Journal of virology Abstract EBV R179A;S186T;K192A 265;272;283 270;277;288 BMRF1;BRLF1 236;147 240;150 16940523 Amino acids in the basic domain of Epstein-Barr virus ZEBRA protein play distinct roles in DNA binding, activation of early lytic gene expression, and promotion of viral DNA replication. Three late mutants, with a Y180A, Y180E, or K188A mutation, were defective at stimulating EBV DNA replication. 2006 Journal of virology Abstract EBV Y180A;Y180E;K188A 27;34;44 32;39;49 16971443 Multivalent sequence recognition by Epstein-Barr virus Zta requires cysteine 171 and an extension of the canonical B-ZIP domain. C171S disrupted Zta transcription activation function of several EBV lytic cycle promoters, including the BMRF1 gene (EA-D) and the other lytic activator, Rta. 2006 Journal of virology Abstract EBV C171S 0 5 BMRF1;BMRF1;BRLF1;BZLF1 106;118;155;16 111;122;158;19 16971443 Multivalent sequence recognition by Epstein-Barr virus Zta requires cysteine 171 and an extension of the canonical B-ZIP domain. Overexpression of Rta could not rescue the C171S defect for transcription reactivation or viral DNA replication. 2006 Journal of virology Abstract EBV C171S 43 48 BRLF1 18 21 16971443 Multivalent sequence recognition by Epstein-Barr virus Zta requires cysteine 171 and an extension of the canonical B-ZIP domain. Purified Zta C171S bound AP-1 sites similar to wild-type Zta, but it was incapable of binding several degenerate Zta sites, including a consensus C/EBP site. 2006 Journal of virology Abstract EBV C171S 13 18 BZLF1;BZLF1;BZLF1 9;57;113 12;60;116 16971443 Multivalent sequence recognition by Epstein-Barr virus Zta requires cysteine 171 and an extension of the canonical B-ZIP domain. We found that serine substitution for cysteine 171 (C171S), which lies outside and amino terminal to the B-ZIP basic region, completely abrogates Zta capacity to initiate lytic cycle replication. 2006 Journal of virology Abstract EBV C171S;C171S 14;52 50;57 BZLF1 146 149 16971443 Multivalent sequence recognition by Epstein-Barr virus Zta requires cysteine 171 and an extension of the canonical B-ZIP domain. Zta C171S was defective for binding to these promoters in vivo, as measured by chromatin immunoprecipitation assay. 2006 Journal of virology Abstract EBV C171S 4 9 BZLF1 0 3 17215287 Phosphoacceptor site S173 in the regulatory domain of Epstein-Barr Virus ZEBRA protein is required for lytic DNA replication but not for activation of viral early genes. An independent assay based on ZEBRA solubility demonstrated a marked defect in DNA binding by the Z(S173A) mutant. 2007 Journal of virology Abstract EBV S173A 100 105 BZLF1;BZLF1 98;30 99;35 17215287 Phosphoacceptor site S173 in the regulatory domain of Epstein-Barr Virus ZEBRA protein is required for lytic DNA replication but not for activation of viral early genes. The phenotype of a phosphomimetic mutant, the Z(S173D) mutant, was similar to that of wild-type ZEBRA. 2007 Journal of virology Abstract EBV S173D 48 53 BZLF1;BZLF1 46;96 47;101 17307213 Point mutations in EBV gH that abrogate or differentially affect B cell and epithelial cell fusion. Substitution of alanine for glutamic acid at residue 595 reduces fusion with epithelial cells, greatly enhances fusion with B cells and allows low levels of B cell fusion even in the absence of gL. 2007 Virology Abstract EBV E595A 16 56 gL 194 196 17307213 Point mutations in EBV gH that abrogate or differentially affect B cell and epithelial cell fusion. Substitution of alanine for glycine at residue 594 completely abrogates fusion with either B cells or epithelial cells. 2007 Virology Abstract EBV G594A 16 50 17854036 Structural variability of the carboxy-terminus of Epstein-Barr virus encoded latent membrane protein 1 gene in Hodgkin's lymphomas. A distinct structural pattern was observed in del30 variants, characterized by a large number of 33 bp repeat units and the presence of a 15 bp insertion encoding the JAK3 Box-1a motif (3/15 wt vs. 16/20 del30; P = 0.001, chi(2) test). 2007 Journal of medical virology Abstract EBV del30 46 51 17854036 Structural variability of the carboxy-terminus of Epstein-Barr virus encoded latent membrane protein 1 gene in Hodgkin's lymphomas. A higher frequency of del30 variant was observed in lymphomas (41/63) than in non-neoplastic controls (6/22) (OR 4.97, CI 95% 1.53-16.79; P = 0.005, chi(2) test). A large number (5-7) of 33 bp repeat units was characteristic of del30 LMP1 variants (P < 0.0001, Fisher's exact test). 2007 Journal of medical virology Abstract EBV del30;del30 228;22 233;27 LMP1 234 238 Lymphoma 52 61 17854036 Structural variability of the carboxy-terminus of Epstein-Barr virus encoded latent membrane protein 1 gene in Hodgkin's lymphomas. EBV association was characterized by EBER-ISH, LMP1 immunohistochemistry and PCR assays for EBNA2 and 3C (typing), LMP1 30 bp deletion (del30) and number of 33 bp tandem repeats. 2007 Journal of medical virology Abstract EBV del30 136 141 EBNA2;LMP1;LMP1 92;47;115 97;51;119 17854036 Structural variability of the carboxy-terminus of Epstein-Barr virus encoded latent membrane protein 1 gene in Hodgkin's lymphomas. The results suggest a pathogenic role for LMP1 del30 variants in Hodgkin's lymphoma from South America and point to particular virus-host molecular mechanisms, such as genomic instability in LMP1 carboxy-terminus, leading to enhanced production and selection of these deletion variants. 2007 Journal of medical virology Abstract EBV del30 47 52 LMP1;LMP1 42;191 46;195 Hodgkin lymphoma 65 83 18297191 Genetic variations of EBV-LMP1 from nasopharyngeal carcinoma biopsies: potential loss of T cell epitopes. Our study discovered that one of the 21 sequence variations harbored a new change at codon 131 (W-->C), and 5/21 specimens showed another novel change at codon 115 (G-->A) in the major epitope sequence of CD8+ T cells restricted by HLA-A2. 2008 Brazilian journal of medical and biological research Abstract EBV G115A;G115A 160;154 171;171 18297191 Genetic variations of EBV-LMP1 from nasopharyngeal carcinoma biopsies: potential loss of T cell epitopes. Results showed that all 21 sequences displayed two amino acid changes most frequently in LMP1 of CD4+ T cell epitopes at codons 144 (F-->I, 21/21) and 212 (G-->S, 19/21) or (G-->N, 2/21). 2008 Brazilian journal of medical and biological research Abstract EBV G212S 151 162 LMP1 89 93 18297191 Genetic variations of EBV-LMP1 from nasopharyngeal carcinoma biopsies: potential loss of T cell epitopes. The other 3 sequences without this deletion all had a change at codon 344 (G-->D). 2008 Brazilian journal of medical and biological research Abstract EBV G344D 64 81 18305033 Epstein-Barr virus immediate-early protein Zta co-opts mitochondrial single-stranded DNA binding protein to promote viral and inhibit mitochondrial DNA replication. A point mutation in the Zta DNA binding domain (C189S), which is known to reduce lytic cycle replication, eliminated mtSSB association with Zta. 2008 Journal of virology Abstract EBV C189S 48 53 BZLF1;BZLF1 24;140 27;143 18318128 [Mutations of the Epstein-Barr virus LMP1 gene mutations in Russian patients with lymphoid pathology and healthy individuals]. Among the point amino avid substitutions, the mutations S366T, F106Y, 185L, and E328Q associated with the enhanced transforming activity of a LMP1 molecule and its reduced cytotoxicity. 2008 Voprosy virusologii Abstract EBV S366T;F106Y;E328Q 56;63;80 61;68;85 LMP1 142 146 18369464 Methylated DNA recognition during the reversal of epigenetic silencing is regulated by cysteine and serine residues in the Epstein-Barr virus lytic switch protein. Here we show that the C189S mutant is defective for activating Rp in a Burkitt's lymphoma cell line. 2008 PLoS pathogens Abstract EBV C189S 22 27 Burkitt lymphoma 71 89 18369464 Methylated DNA recognition during the reversal of epigenetic silencing is regulated by cysteine and serine residues in the Epstein-Barr virus lytic switch protein. Zta's ability to trigger lytic cycle activation is severely compromised when a cysteine residue in its bZIP domain is mutated to serine (C189S), but the molecular basis for this effect is unknown. 2008 PLoS pathogens Abstract EBV C189S 137 142 BZLF1 0 3 18631132 The reversal of epigenetic silencing of the EBV genome is regulated by viral bZIP protein. A single point mutant of Zta, C189S, is defective in binding to the methylated ZREs both in vitro and in vivo. 2008 Biochemical Society transactions Abstract EBV C189S 30 35 BZLF1 25 28 18631132 The reversal of epigenetic silencing of the EBV genome is regulated by viral bZIP protein. ZtaC189S was not able to activate Rp in a B-cell line, demonstrating the relevance of the interaction with methylated ZREs. 2008 Biochemical Society transactions Abstract EBV C189S 3 8 BZLF1 0 3 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. Co-expression of Rta with S186A mutant rescued diffuse EA-D but not globular replication compartments. 2008 Virology Abstract EBV S186A 26 31 BMRF1;BRLF1 55;17 59;20 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. The distribution of S186A mutant ZEBRA protein, defective for activation of Rta and EA-D, was identical to WT, except that the mutant ZEBRA was never found in globular compartments. 2008 Virology Abstract EBV S186A 20 25 BMRF1;BRLF1;BZLF1;BZLF1 84;76;33;134 88;79;38;139 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. The distribution of ZEBRA and EA-D proteins was identical to WT following transfection of K188R, a mutant with a conservative change. 2008 Virology Abstract EBV K188R 90 95 BMRF1;BZLF1 30;20 34;25 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. The most striking observation was that several mutant ZEBRA proteins defective in activating EA-D (R179A, K181A and A185V) and defective in activating lytic viral DNA replication and late genes (Y180E and K188A) were localized to numerous punctate foci. 2008 Virology Abstract EBV R179A;K181A;A185V;Y180E;K188A 99;106;116;195;205 104;111;121;200;210 BMRF1;BZLF1 93;54 97;59 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. The speckled appearance of R179A and Y180E was more regular and clearly defined in EBV-positive than in EBV-negative 293 cells. 2008 Virology Abstract EBV R179A;Y180E 27;37 32;42 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. The Y180E late-mutant induced EA-D, but prevented EA-D from localizing to globular replication compartments. 2008 Virology Abstract EBV Y180E 4 9 BMRF1;BMRF1 30;50 34;54 18986987 Tumor-derived variants of Epstein-Barr virus latent membrane protein 1 induce sustained Erk activation and c-Fos. Point mutation of either amino acids 212 (glycine to serine) or 366 (serine to threonine) from the B95.8 isoform to the tumor variant version of LMP1 was sufficient for gain of function characterized by sustained activation of Erk and subsequent c-Fos induction and binding to the AP1 site. 2008 The Journal of biological chemistry Abstract EBV G212S;S366T 37;64 60;89 LMP1 145 149 19144704 Interaction of Epstein-Barr virus BZLF1 C-terminal tail structure and core zipper is required for DNA replication but not for promoter transactivation. The restoration of BZLF1 DNA replication activity by the complementation of two deleterious mutations (S208E and D236K) indicates that the interaction of the C-terminal tail and the core zipper is required for DNA replication, identifying a functional role for this structural feature unique to BZLF1. 2009 Journal of virology Abstract EBV S208E;D236K 103;113 108;118 BZLF1;BZLF1 19;295 24;300 19211641 Comparative analysis of oncogenic properties and nuclear factor-kappaB activity of latent membrane protein 1 natural variants from Hodgkin's lymphoma's Reed-Sternberg cells and normal B-lymphocytes. RESULTS: LMP1 variants of Reed-Sternberg cell origin were often associated with increased mutation rate and with recurrent genetic events, such as del15bp associated with S to N replacement at codon 309, and four substitutions I85L, F106Y, I122L, and M129I. 2009 Haematologica Abstract EBV del15bp;I85L;F106Y;I122L;M129I 147;227;233;240;251 154;231;238;245;256 LMP1 9 13 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. Alanine substitution mutants, F600A/F605A, abolished activity of the DBIS. 2009 Virology Abstract EBV F600A;F605A 30;36 35;41 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. Alanine substitutions, F600A/F605A, decreased transcriptional activation by Rta protein, whereas aromatic substitutions, such as F600Y/F605Y or F600W/F605W, partially restored transcriptional activation. 2009 Virology Abstract EBV F600A;F605A;F600Y;F605Y;F600W;F605W 23;29;129;135;144;150 28;34;134;140;149;155 BRLF1 76 79 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. Full-length Rta protein with F600A/F605A mutations were enhanced in DNA binding compared to wild-type, whereas Rta proteins with F600Y/F605Y or F600W/F605W substitutions were, like wild-type Rta, relatively poor DNA binders. 2009 Virology Abstract EBV F600A;F605A;F600Y;F605Y;F600W;F605W 29;35;129;135;144;150 34;40;134;140;149;155 BRLF1;BRLF1;BRLF1 12;111;191 15;114;194 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. GAL4 (1-147)/Rta (416-605) fusion proteins with F600A/F605A mutations were diminished in transcriptional activation, relative to GAL4/Rta chimeras without such mutations. 2009 Virology Abstract EBV F600A;F605A 48;54 53;59 BRLF1;BRLF1 13;134 16;137 19244336 The Epstein-Barr virus (EBV) deubiquitinating enzyme BPLF1 reduces EBV ribonucleotide reductase activity. Finally, expression of enzymatically active BPLF1 1-246 decreased RR activity, whereas a nonfunctional active-site mutant (BPLF1 C61S) had no effect. 2009 Journal of virology Abstract EBV C61S 129 133 BPLF1;BPLF1 44;123 49;128 19321754 Epstein-Barr virus protein kinase BGLF4 interacts with viral transactivator BZLF1 and regulates its transactivation activity. In the present study, it was demonstrated that alanine substitution of the serine residue at position 209 (S209A) in BZLF1 eliminated phosphorylation of the protein by BGLF4 in vitro. 2009 The Journal of general virology Abstract EBV S209A;S209A 47;107 105;112 BGLF4;BZLF1 168;117 173;122 19321754 Epstein-Barr virus protein kinase BGLF4 interacts with viral transactivator BZLF1 and regulates its transactivation activity. The S209A mutation in BZLF1, as well as a K102I mutation in BGLF4, which inactivated catalytic activity of the viral kinase, also inhibited formation of a stable BGLF4-BZLF1 complex and downregulation of BZLF1 autotransactivation activity mediated by BGLF4. 2009 The Journal of general virology Abstract EBV S209A;K102I 4;42 9;47 BGLF4;BGLF4;BGLF4;BZLF1;BZLF1;BZLF1 60;162;251;22;168;204 65;167;256;27;173;209 19325883 Methylation-dependent binding of the epstein-barr virus BZLF1 protein to viral promoters. The Z(S186A) mutant cannot activate methylated Nap in reporter gene assays and does not induce Na expression in cells with latent EBV infection. 2009 PLoS pathogens Abstract EBV S186A 6 11 BZLF1 4 5 EBV infections 130 143 19491105 Epstein-Barr virus polymerase processivity factor enhances BALF2 promoter transcription as a coactivator for the BZLF1 immediate-early protein. A monomeric mutant, C95E, which is defective in homodimerization, could still interact and enhance BZLF1-mediated transactivation. 2009 The Journal of biological chemistry Abstract EBV C95E 20 24 BZLF1 99 104 19801550 Crystal structure of epstein-barr virus DNA polymerase processivity factor BMRF1. Although the R87E and H141F mutants of BMRF1-DeltaC exhibited dramatically reduced polymerase processivity, they were still able to bind DNA and to dimerize. 2009 The Journal of biological chemistry Abstract EBV R87E;H141F 13;22 17;27 BMRF1 39 44 19801550 Crystal structure of epstein-barr virus DNA polymerase processivity factor BMRF1. The C95E mutant, which disrupts dimer formation, lacked DNA binding activity, indicating that dimer formation is required for DNA binding. 2009 The Journal of biological chemistry Abstract EBV C95E 4 8 20516063 Transcriptional repression by sumoylation of Epstein-Barr virus BZLF1 protein correlates with association of histone deacetylase. The K12R mutant of BZLF1, which no longer becomes sumoylated, exhibits stronger transactivation than the wild-type BZLF1 in a reporter assay system as well as in the context of virus genome with nucleosomal structures. 2010 The Journal of biological chemistry Abstract EBV K12R 4 8 BZLF1;BZLF1 19;115 24;120 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. A ZEBRA mutant, Z(S173A), at a phosphorylation site and three point mutants in the DNA recognition domain of ZEBRA, namely Z(Y180E), Z(R187K) and Z(K188A), were similarly deficient at activating lytic DNA replication and expression of late gene expression but were competent to activate transcription of viral early lytic genes. 2010 PLoS pathogens Abstract EBV S173A;Y180E;R187K;K188A 18;125;135;148 23;130;140;153 BZLF1;BZLF1;BZLF1;BZLF1;BZLF1;BZLF1 16;123;133;146;2;109 17;124;134;147;7;114 20849661 Conserved mutation of Epstein-Barr virus-encoded BamHI-A Rightward Frame-1 (BARF1) gene in Indonesian nasopharyngeal carcinoma. At the protein level these mutations resulted in 3 main substitutions (V29A, W72G, H130R), which are not considered to cause gross tertiary structure alterations in the hexameric BARF1 protein. 2010 Infectious agents and cancer Abstract EBV V29A;W72G;H130R 71;77;83 75;81;88 BARF1 179 184 20861254 The Epstein-Barr virus BZLF1 protein inhibits tumor necrosis factor receptor 1 expression through effects on cellular C/EBP proteins. Furthermore, we find that the Z(A204D) mutant is attenuated in the ability to inhibit the TNFR1p but mediates lytic viral reactivation and replication in vitro in 293 cells as well as wild-type Z. 2010 Journal of virology Abstract EBV A204D 32 37 BZLF1;BZLF1 30;194 31;195 20861254 The Epstein-Barr virus BZLF1 protein inhibits tumor necrosis factor receptor 1 expression through effects on cellular C/EBP proteins. The Z(A204D) mutant has reduced interaction with the TNFR1p in vivo but is similar to wild-type Z in its ability to complex with the IL-8 promoter. 2010 Journal of virology Abstract EBV A204D 6 11 BZLF1;BZLF1 4;96 5;97 20926567 Tetrameric ring formation of Epstein-Barr virus polymerase processivity factor is crucial for viral replication. Also, surprisingly, replication of the C206E virus, which is expected to have impairment of tail-to-tail contact, was severely restricted, although the mutant protein possesses the same in vitro biochemical activities as the wild type. 2010 Journal of virology Abstract EBV C206E 39 44 20926567 Tetrameric ring formation of Epstein-Barr virus polymerase processivity factor is crucial for viral replication. The R256E virus, which has a severely impaired capacity for DNA binding and polymerase processivity, failed to form replication compartments, resulting in interference of viral replication, while the C95E mutation, which impairs head-to-head contact in vitro, unexpectedly hardly affected the viral replication. 2010 Journal of virology Abstract EBV R256E;C95E 4;200 9;204 21114920 Polymorphisms of Epstein-Barr virus BHRF1 gene, a homologue of bcl-2. Based on the mutations at AA88 and AA79, 3 distinct variants of BHRF1 genes, designated as 79V88V, 79L88L, and 79V88L, were identified. 2010 Chinese journal of cancer Abstract EBV V79L;L88V 99;91 105;97 BHRF1 64 69 21123379 The Epstein-Barr virus-encoded BILF1 protein modulates immune recognition of endogenously processed antigen by targeting major histocompatibility complex class I molecules trafficking on both the exocytic and endocytic pathways. We now demonstrate that disruption of the EKT signaling motif of BILF1 by a K122A mutation impairs the ability of BILF1 to enhance endocytosis of surface MHC-I molecules, while subsequent lysosomal degradation was impaired by deletion of the 21-residue C-terminal tail of BILF1. 2011 Journal of virology Abstract EBV K122A 76 81 BILF1;BILF1;BILF1 65;114;272 70;119;277 21209116 Roscovitine inhibits EBNA1 serine 393 phosphorylation, nuclear localization, transcription, and episome maintenance. Further, S393A mutation abrogated phosphorylation. 2011 Journal of virology Abstract EBV S393A 9 14 21209116 Roscovitine inhibits EBNA1 serine 393 phosphorylation, nuclear localization, transcription, and episome maintenance. Moreover, roscovitine decreased nuclear EBNA1 and often increased cytoplasmic EBNA1, whereas S393A mutant EBNA1 was localized equally in the nucleus and cytoplasm and was unaffected by roscovitine treatment. 2011 Journal of virology Abstract EBV S393A 93 98 EBNA1;EBNA1;EBNA1 40;78;106 45;83;111 21209116 Roscovitine inhibits EBNA1 serine 393 phosphorylation, nuclear localization, transcription, and episome maintenance. S393A mutant EBNA1 was deficient in supporting EBNA1- and oriP-dependent transcription and episome persistence, and roscovitine had little further effect on the diminished S393A mutant EBNA1-mediated transcription or episome persistence. 2011 Journal of virology Abstract EBV S393A;S393A 0;172 5;177 EBNA1;EBNA1;EBNA1 13;47;185 18;52;190 21233201 Efficient induction of nuclear aggresomes by specific single missense mutations in the DNA-binding domain of a viral AP-1 homolog. Co-transfection of WT ZEBRA with aggresome-inducing mutants Z(R183E) and Z(R179E) inhibited late lytic viral protein expression and lytic viral DNA amplification. 2011 The Journal of biological chemistry Abstract EBV R183E;R179E 62;75 67;80 BZLF1;BZLF1;BZLF1 60;73;22 61;74;27 21233201 Efficient induction of nuclear aggresomes by specific single missense mutations in the DNA-binding domain of a viral AP-1 homolog. Four non-DNA-binding mutants, Z(R179E), Z(R183E), Z(R190E), and Z(K178D) localized to the periphery of large intranuclear spheres, to discrete nuclear aggregates, and to the cytoplasm. 2011 The Journal of biological chemistry Abstract EBV R179E;R183E;R190E;K178D 32;42;52;66 37;47;57;71 BZLF1;BZLF1;BZLF1;BZLF1 30;40;50;64 31;41;51;65 21233201 Efficient induction of nuclear aggresomes by specific single missense mutations in the DNA-binding domain of a viral AP-1 homolog. Other non-DNA-binding mutants, Z(N182K), Z(N182E), and Z(S186E), did not exhibit this phenotype. 2011 The Journal of biological chemistry Abstract EBV N182K;N182E;S186E 33;43;57 38;48;62 BZLF1;BZLF1;BZLF1 31;41;55 32;42;56 21440926 Epstein-Barr virus nuclear protein 3C binds to the N-terminal (NTD) and beta trefoil domains (BTD) of RBP/CSL; only the NTD interaction is essential for lymphoblastoid cell growth. Further, an EBNA3C WTP STP(W227S) mutation impaired BTD binding whereas EBNA3 homology domain mutations disrupted RBP/CSL N-terminal domain (NTD) binding. 2011 Virology Abstract EBV W227S 27 32 EBNA3C;EBNA3 12;72 18;77 21560118 Transmembrane peptides used to investigate the homo-oligomeric interface and binding hotspot of latent membrane protein 1. A full-length LMP-1 variant harboring the D150A substitution is deficient in NFkappaB activation, supporting the key role of the fifth transmembrane helix in constitutive activation of signaling by this oncoprotein. 2011 Biopolymers Abstract EBV D150A 42 47 LMP1 14 19 21697476 Cellular transcription factor Oct-1 interacts with the Epstein-Barr virus BRLF1 protein to promote disruption of viral latency. In addition, we demonstrate that an Oct-1 mutant defective in DNA binding (the S335D mutant) still retains the ability to enhance BRLF1 transcriptional effects. 2011 Journal of virology Abstract EBV S335D 79 84 BRLF1 130 135 21697476 Cellular transcription factor Oct-1 interacts with the Epstein-Barr virus BRLF1 protein to promote disruption of viral latency. We find that Oct-1 interacts directly with BRLF1 in vitro and that a mutant BRLF1 protein (the M140A mutant) attenuated for the ability to interact with Oct-1 in vitro is also resistant to Oct-1-mediated transcriptional enhancement in 293 BRLF1-stop cells. 2011 Journal of virology Abstract EBV M140A 95 100 BRLF1;BRLF1;BRLF1 43;76;239 48;81;244 22348267 Sequence analysis of Epstein-Barr virus EBNA-2 gene coding amino acid 148-487 in nasopharyngeal and gastric carcinomas. Three variations (g48991t, c48998a, t49613a) were detected in all of the samples (113/113, 100%). 2012 Virology journal Abstract EBV G48991T;C48998A;T49613A 18;27;36 25;34;43 22348267 Sequence analysis of Epstein-Barr virus EBNA-2 gene coding amino acid 148-487 in nasopharyngeal and gastric carcinomas. Variation analysis in EBNA-2 functional domains: the TAD residue (I438L) and the NLS residues (E476G, P484H and I486T) were only detected in NPC samples which located in the carboxyl terminus of EBNA-2 gene. 2012 Virology journal Abstract EBV I438L;E476G;P484H;I486T 66;95;102;112 71;100;107;117 EBNA2;EBNA2 22;195 28;201 Nasopharyngeal carcinoma 141 144 22379087 Genome-wide analysis of Epstein-Barr virus Rta DNA binding. Rta K156A failed to activate BALF5p, suggesting this promoter can be activated by an RRE-dependent mechanism. 2012 Journal of virology Abstract EBV K156A 4 9 BRLF1 0 3 22379087 Genome-wide analysis of Epstein-Barr virus Rta DNA binding. To assess whether BALF5 might be activated by an RRE-dependent mechanism, an Rta mutant (Rta K156A), deficient for DNA binding and RRE activation but competent for Zp/Rp activation, was used. 2012 Journal of virology Abstract EBV K156A 93 98 BALF5;BRLF1;BRLF1;BZLF1 promoter 18;77;89;164 23;80;92;166 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. F106Y was present in all LMP1 isolated in this study and its effect was variant dependent, suggesting that it was modulated by other polymorphisms. 2012 PloS one Abstract EBV F106Y 0 5 LMP1 25 29 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. The two polymorphisms I124V and F144I were present in distinct phylogenetic groups and were linked with other specific polymorphisms nearby, I152L and D150A/L151I, respectively. 2012 PloS one Abstract EBV I124V;F144I;I152L;D150A;L151I 22;32;141;151;157 27;37;146;155;162 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. The two sets of polymorphisms, I124V/I152L and F144I/D150A/L151I, which were markers of increased NF-kappaB activation in vitro, were not associated with EBV-associated HL in the SHCS. 2012 PloS one Abstract EBV I124V;I152L;F144I;D150A;L151I 31;37;47;53;59 36;42;52;58;64 Hodgkin lymphoma 169 171 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. We found that a number of variants mediate higher NF-kappaB activation levels when compared to B95-8 LMP1 and mapped three single polymorphisms responsible for this phenotype: F106Y, I124V and F144I. 2012 PloS one Abstract EBV F106Y;I124V;F144I 176;183;193 181;188;198 LMP1 101 105 22406129 Unique variations of Epstein-Barr virus-encoded BARF1 gene in nasopharyngeal carcinoma biopsies. The relatively higher prevalence of type f/V29A/SPM strains in NPC may also suggest the association between these variations in multiple viral genes and NPC. 2012 Virus research Abstract EBV V29A 43 47 Nasopharyngeal carcinoma;Nasopharyngeal carcinoma 63;153 66;156 22406129 Unique variations of Epstein-Barr virus-encoded BARF1 gene in nasopharyngeal carcinoma biopsies. Two major subtypes of BARF1 gene, designated as B95-8 and V29A, were identified. 2012 Virus research Abstract EBV V29A 58 62 BARF1 22 27 22406129 Unique variations of Epstein-Barr virus-encoded BARF1 gene in nasopharyngeal carcinoma biopsies. Type f isolates was specially correlated with the V29A/SPM genotype in NPC isolates and type f/V29A/SPM was preferentially found in NPC. 2012 Virus research Abstract EBV V29A;V29A 50;95 54;99 Nasopharyngeal carcinoma;Nasopharyngeal carcinoma 132;71 135;74 22406129 Unique variations of Epstein-Barr virus-encoded BARF1 gene in nasopharyngeal carcinoma biopsies. V29A subtype, with one consistent amino acid change at residue 29 (V A) and several nucleotide changes, showed higher frequency in NPC cases (25.3%, 20/79) than in EBVaGC cases (0/45) or healthy donors (4.3%, 2/46) (NPC vs. 2012 Virus research Abstract EBV V29A 0 4 Nasopharyngeal carcinoma;Nasopharyngeal carcinoma;Gastric carcinoma 131;216;164 134;219;170 22590638 Genomic sequencing and comparative analysis of Epstein-Barr virus genome isolated from primary nasopharyngeal carcinoma biopsy. Variations in LMP1 and EBNA3B epitopes and mutations in Cp (11404 C>T) and Qp (50134 G>C) found in GD1, GD2 and HKNPC1 could potentially affect CD8(+) T cell recognition and latent gene expression pattern in NPC, respectively. 2012 PloS one Abstract EBV C11404T;G50134C 60;79 69;88 EBNA3B;LMP1 23;14 29;18 Nasopharyngeal carcinoma 208 211 23077295 Essential role of Rta in lytic DNA replication of Epstein-Barr virus. Ectopic expression of the six components of the EBV lytic replication machinery failed to rescue replication by Z(S186A). 2013 Journal of virology Abstract EBV S186A 114 119 BZLF1 112 113 23077295 Essential role of Rta in lytic DNA replication of Epstein-Barr virus. However, addition of Rta to Z(S186A) and the mixture of replication factors activated viral replication and late gene expression. 2013 Journal of virology Abstract EBV S186A 30 35 BRLF1;BZLF1 21;28 24;29 23077295 Essential role of Rta in lytic DNA replication of Epstein-Barr virus. In addition, expression of Rta and Z(S186A) together, but not individually, activated synthesis of the BHLF1 transcript, a lytic transcript required for the process of viral DNA replication. 2013 Journal of virology Abstract EBV S186A 37 42 BHLF1;BRLF1;BZLF1 103;27;35 108;30;36 23077295 Essential role of Rta in lytic DNA replication of Epstein-Barr virus. We found that Z(S186A), a mutant of ZEBRA unable to activate transcription of Rta or viral genes encoding replication proteins, is competent to bind to oriLyt and to function as an origin recognition protein. 2013 Journal of virology Abstract EBV S186A 16 21 BRLF1;BZLF1;BZLF1 78;14;36 81;15;41 23221557 Pin1 interacts with the Epstein-Barr virus DNA polymerase catalytic subunit and regulates viral DNA replication. Exogenous supply of wild-type BALF5 in HEK293 cells with knockout recombinant EBV allowed efficient synthesis of viral genome DNA, but BALF5 T178A could not provide support as efficiently as wild-type BALF5. 2013 Journal of virology Abstract EBV T178A 141 146 BALF5;BALF5;BALF5 30;135;201 35;140;206 23221557 Pin1 interacts with the Epstein-Barr virus DNA polymerase catalytic subunit and regulates viral DNA replication. Lambda protein phosphatase treatment abolished the binding of BALF5 to Pin1, and mutation analysis of BALF5 revealed that replacement of the Thr178 residue by Ala (BALF5 T178A) disrupted the interaction with Pin1. 2013 Journal of virology Abstract EBV T178A;T178A 170;141 175;162 BALF5;BALF5;BALF5 62;102;164 67;107;169 23325693 The large groove found in the gH/gL structure is an important functional domain for Epstein-Barr virus fusion. We also observed that substitution of alanine for arginine 152, histidine 154, or threonine 174 reduces fusion with epithelial cells but not with B cells. 2013 Journal of virology Abstract EBV R152A 38 62 23325693 The large groove found in the gH/gL structure is an important functional domain for Epstein-Barr virus fusion. We found that substitution of alanine for leucine 207 reduces both epithelial and B cell fusion and is accompanied by reduced gp42 binding. 2013 Journal of virology Abstract EBV L207A 30 53 23325693 The large groove found in the gH/gL structure is an important functional domain for Epstein-Barr virus fusion. We found that the G49C mutant, predicted to bridge D-I and D-II with C153 of gH/gL, had normal B cell fusion activity but reduced epithelial cell fusion activity, which was partially restored by treatment with dithiothreitol. 2013 Journal of virology Abstract EBV G49C 18 22 gH;gL 77;80 79;82 24009107 Epstein-barr virus latent membrane protein 1 polymorphism in nasopharyngeal carcinoma and other oral cavity tumors in Russia. In particular, the G212S substitution in LMP1 isolates investigated was not observed at all. 2014 Journal of medical virology Abstract EBV G212S 19 24 LMP1 41 45 24016332 Identification of a novel variant of LMP-1 of EBV in patients with endemic Burkitt lymphoma in western Kenya. However a novel LMP-1 variant was identified, called K for Kenya and for the G318K mutation that characterizes it. 2013 Infectious agents and cancer Abstract EBV G318K 77 82 LMP1 16 21 24075898 High molecular weight complex analysis of Epstein-Barr virus Latent Membrane Protein 1 (LMP-1): structural insights into LMP-1's homo-oligomerization and lipid raft association. LMP-1/C238A retains wild type LMP-1 NF-kappaB activity. 2013 Virus research Abstract EBV C238A 6 11 LMP1;LMP1 0;30 5;35 24705134 Nuclear translocation and regulation of intranuclear distribution of cytoplasmic poly(A)-binding protein are distinct processes mediated by two Epstein Barr virus proteins. One ZEBRA mutant, Z(S186E), was deficient in translocation yet was capable of altering the intranuclear distribution of PABPC. 2014 PloS one Abstract EBV S186E 20 25 BZLF1;BZLF1 18;4 19;9 24872582 Uracil DNA glycosylase BKRF3 contributes to Epstein-Barr virus DNA replication through physical interactions with proteins in viral DNA replication complex. In complementation assays, the catalytic mutant BKRF3(Q90L,D91N) restored viral DNA replication, whereas the leucine loop mutant BKRF3(H213L) only partially rescued viral DNA replication, coupled with a reduced ability to interact with the viral DNA polymerase and Rta. 2014 Journal of virology Abstract EBV Q90L;D91N;H213L 54;59;135 58;63;140 BKRF3;BKRF3;BRLF1 48;129;265 53;134;268 25865256 Exosomal sorting of the viral oncoprotein LMP1 is restrained by TRAF2 association at signalling endosomes. Notably, growth assays in soft agar revealed that oncogenic properties of the palmitoylation-deficient LMP1 mutant C78A were diminished compared to wild-type LMP1. 2015 Journal of extracellular vesicles Abstract EBV C78A 115 119 LMP1;LMP1 103;158 107;162 25900136 RanBPM regulates Zta-mediated transcriptional activity in Epstein-Barr virus. Interestingly, Z-K12R, a sumoylation-defective mutant of Zta, demonstrated transcriptional activation capabilities that were stronger than those of Zta and apparently unaffected by RanBPM modulation. 2015 The Journal of general virology Abstract EBV K12R 16 21 BZLF1;BZLF1;BZLF1 57;148;15 60;151;16 25950714 DNA Damage Signaling Is Induced in the Absence of Epstein-Barr Virus (EBV) Lytic DNA Replication and in Response to Expression of ZEBRA. ZEBRA mutants deficient in DNA binding, Z(R183E) and Z(S186E), did not induce foci of pATM. 2015 PloS one Abstract EBV R183E;S186E 42;55 47;60 BZLF1;BZLF1;BZLF1 0;40;53 5;41;54 26337172 Sequence analysis of Epstein-Barr virus (EBV) early genes BARF1 and BHRF1 in NK/T cell lymphoma from Northern China. It has been found that V29A strains, a BARF1 mutant subtype, showed higher prevalence in NPC, which may suggest the association between this variation and nasopharyngeal carcinoma (NPC). 2015 Virology journal Abstract EBV V29A 23 27 BARF1 39 44 Nasopharyngeal carcinoma;Nasopharyngeal carcinoma;Nasopharyngeal carcinoma 89;155;181 92;179;184 26337172 Sequence analysis of Epstein-Barr virus (EBV) early genes BARF1 and BHRF1 in NK/T cell lymphoma from Northern China. RESULTS: Two major subtypes of BARF1 gene, designated as B95-8 and V29A subtype, were identified. 2015 Virology journal Abstract EBV V29A 67 71 BARF1 31 36 26337172 Sequence analysis of Epstein-Barr virus (EBV) early genes BARF1 and BHRF1 in NK/T cell lymphoma from Northern China. The V29A subtype had one consistent amino acid change at amino acid residue 29 (V A). 2015 Virology journal Abstract EBV V29A 4 8 26675171 A single nucleotide polymorphism in the Epstein-Barr virus genome is strongly associated with a high risk of nasopharyngeal carcinoma. Moreover, the frequency of the SNP G155391A was associated with NPC incidence but was not associated with the incidences of other EBV-related malignancies. 2015 Chinese journal of cancer Abstract EBV G155391A 35 43 Nasopharyngeal carcinoma;EBV-related malignancy 64;130 67;154 26675171 A single nucleotide polymorphism in the Epstein-Barr virus genome is strongly associated with a high risk of nasopharyngeal carcinoma. RESULTS: Based on EBV-encoded RPMS1 variations, a single nucleotide polymorphism (SNP) in the EBV genome (locus 155391: G>A, named G155391A) was associated with NPC in 157 cases and 319 healthy controls from an NPC endemic region in South China [P < 0.001, odds ratio (OR) = 4.47, 95% confidence interval (CI) 2.71-7.37]. 2015 Chinese journal of cancer Abstract EBV G155391A 131 139 RPMS1 30 35 Nasopharyngeal carcinoma;Nasopharyngeal carcinoma 161;211 164;214 26675171 A single nucleotide polymorphism in the Epstein-Barr virus genome is strongly associated with a high risk of nasopharyngeal carcinoma. The combined analysis in 1109 cases and 2052 controls revealed that the SNP G155391A was strongly associated with NPC (P(combined) < 0.001, OR = 5.27, 95% CI 4.31-6.44). 2015 Chinese journal of cancer Abstract EBV G155391A 76 84 Nasopharyngeal carcinoma 114 117 27009860 ERK2 phosphorylation of EBNA1 serine 383 residue is important for EBNA1-dependent transactivation. In accordance, ERK2 was found to phosphorylate EBNA1 serine 383 in a reaction suppressed by H20 (a structural congener of the ERK inhibitor), U0126 (an inhibitor of MEK kinase), and mutations at substrate (S383A) or putative ERK docking sites. 2016 Oncotarget Abstract EBV S383A 206 211 EBNA1 47 52 27009860 ERK2 phosphorylation of EBNA1 serine 383 residue is important for EBNA1-dependent transactivation. Wild-type (S383) and phosphomimetic (S383D) EBNA1 demonstrated comparable transactivation function, which was suppressed by H20 or U0126. 2016 Oncotarget Abstract EBV S383D 37 42 EBNA1 44 49 27061907 Clonal deleted latent membrane protein 1 variants of Epstein-Barr virus are predominant in European extranodal NK/T lymphomas and disappear during successful treatment. These results suggest that del30 may be associated with poor prognosis NK/TL and that strain evolution could be used as a potential marker to monitor treatment. 2016 International journal of cancer Abstract EBV del30 27 32 28956769 Epstein-Barr Virus Fusion with Epithelial Cells Triggered by gB Is Restricted by a gL Glycosylation Site. Our previous study found that the gL glycosylation mutant N69L/S71V had an epithelial cell-specific hyperfusogenic phenotype. 2017 Journal of virology Abstract EBV N69L;S71V 58;63 62;67 gL 34 36 28956769 Epstein-Barr Virus Fusion with Epithelial Cells Triggered by gB Is Restricted by a gL Glycosylation Site. The gL_N69L/S71V mutant had a large increase in epithelial cell fusion activity of up to 300% greater than that of wild-type gL starting at early time points. 2017 Journal of virology Abstract EBV S71V;N69L 12;7 16;11 gL;gL 4;125 6;127 29221111 Nasopharyngeal carcinoma risk prediction via salivary detection of host and Epstein-Barr virus genetic variants. In this study, in southern China, where NPC is endemic, a single nucleotide polymorphism (SNP) in the EBV-encoded RPMS1 gene (locus 155391: G > A [G155391A]) and seven host SNPs (rs1412829, rs28421666, rs2860580, rs2894207, rs31489, rs6774494, and rs9510787) were confirmed to be significantly associated with NPC risk in 50 NPC cases versus 54 hospital-based controls with throat washing specimens and 1925 NPC cases versus 1947 hospital-based controls with buffy coat samples, respectively. 2017 Oncotarget Abstract EBV G155391A 147 155 RPMS1 114 119 Nasopharyngeal carcinoma;Nasopharyngeal carcinoma;Nasopharyngeal carcinoma;Nasopharyngeal carcinoma 40;310;325;408 43;313;328;411 29665370 Conservation and polymorphism of EBV RPMS1 gene in EBV-associated tumors and healthy individuals from endemic and non-endemic nasopharyngeal carcinoma areas in China. However, few studies have investigated the single-nucleotide polymorphisms (SNPs) of RPMS1, and only one SNP site (g155391a) has been reported to be associated with nasopharyngeal carcinoma occurrence. 2018 Virus research Abstract EBV G155391A 115 123 RPMS1 85 90 Nasopharyngeal carcinoma 165 189 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. Binding of Zta(C189S) and Zta(C189T) to DNA containing modified cytosines (DNA(5mC|C), DNA(5hmC|C), and DNA(5mCG)) was reduced compared to Zta. 2018 Biochemical and biophysical research communications Abstract EBV C189S;C189T 15;30 20;35 BZLF1;BZLF1;BZLF1 11;26;139 14;29;142 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. Substitution of cysteine 189 of Zta to serine (Zta(C189S)) results in a virus that is unable to execute the lytic cycle, which was attributed to a change in binding to methylated DNA sequences. 2018 Biochemical and biophysical research communications Abstract EBV C189S 51 56 BZLF1;BZLF1 32;47 35;50 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. To learn more about the role of this position in defining sequence-specific DNA binding, we mutated cysteine 189 to four other amino acids, producing Zta(C189S), Zta(C189T), Zta(C189A), and Zta(C189V) mutants. 2018 Biochemical and biophysical research communications Abstract EBV C189S;C189T;C189A;C189V 154;166;178;194 159;171;183;199 BZLF1;BZLF1;BZLF1;BZLF1 150;162;174;190 153;165;177;193 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. Zta(C189A) and Zta(C189V) had higher non-specific binding to all four types of DNA. 2018 Biochemical and biophysical research communications Abstract EBV C189A;C189V 4;19 9;24 BZLF1;BZLF1 0;15 3;18 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. Zta(C189S) and Zta(C189T) bound the TRE (AP-1) motif (TGAG/CTCA) more strongly than wild-type Zta, while binding to other sequences, including the C/EBP half site GCAA was reduced. 2018 Biochemical and biophysical research communications Abstract EBV C189S;C189T 4;19 9;24 BZLF1;BZLF1;BZLF1 0;15;94 3;18;97 29797589 Sequence variations of Epstein-Barr virus-encoded BARF1 gene in nasopharyngeal carcinomas and healthy donors from southern and northern China. For Chinese isolates, the B95-8 type was dominant in both southern and northern China, but the isolates from southern China showed a higher frequency of the B95-8t165545c subtype than the isolates from northern China (76.0%, 38/50 NPC cases and 50.7%, 37/73 healthy donors vs 26.4%, 24/91 NPC cases and 7.6%, 6/79 healthy donors, P < .0001). 2018 Journal of medical virology Abstract EBV T165545C 162 170 Nasopharyngeal carcinoma;Nasopharyngeal carcinoma 231;289 234;292 29797589 Sequence variations of Epstein-Barr virus-encoded BARF1 gene in nasopharyngeal carcinomas and healthy donors from southern and northern China. For EBV genomes, the B95-8P subtype was dominant in northern China, Europe, America, and Australia, while V29A was dominant in Africa. 2018 Journal of medical virology Abstract EBV V29A 106 110 29797589 Sequence variations of Epstein-Barr virus-encoded BARF1 gene in nasopharyngeal carcinomas and healthy donors from southern and northern China. Furthermore, the B95-8t165545c subtype was more frequent in NPC cases than healthy donors in both southern China (P = .005) and northern China (P = .001). 2018 Journal of medical virology Abstract EBV T165545C 22 30 Nasopharyngeal carcinoma 60 63 29797589 Sequence variations of Epstein-Barr virus-encoded BARF1 gene in nasopharyngeal carcinomas and healthy donors from southern and northern China. Only 1 consistent coding change, V29A, and several consistent silent mutations were identified. 2018 Journal of medical virology Abstract EBV V29A 33 37 29797589 Sequence variations of Epstein-Barr virus-encoded BARF1 gene in nasopharyngeal carcinomas and healthy donors from southern and northern China. The B95-8t165545c subtype was only identified in Asia and demonstrated high frequency (81.2%, 26/32) in genomes from NPC cases in southern China. 2018 Journal of medical virology Abstract EBV T165545C 9 17 Nasopharyngeal carcinoma 117 120 29797589 Sequence variations of Epstein-Barr virus-encoded BARF1 gene in nasopharyngeal carcinomas and healthy donors from southern and northern China. These results further reveal conservation and possibly geographically spread variations of BARF1 and may also indicate the preference of EBV strains with the B95-8t165545c subtype in NPC cases, without biological or pathogenic implications. 2018 Journal of medical virology Abstract EBV T165545C 163 171 BARF1 91 96 Nasopharyngeal carcinoma 183 186 29797589 Sequence variations of Epstein-Barr virus-encoded BARF1 gene in nasopharyngeal carcinomas and healthy donors from southern and northern China. Two BARF1 types (B95-8 and V29A) and 2 B95-8 subtypes (B95-8t165545c and B95-8P ) were classified. 2018 Journal of medical virology Abstract EBV T165545C;V29A 60;27 68;31 BARF1 4 9 31481499 Integrated Pan-Cancer Map of EBV-Associated Neoplasms Reveals Functional Host-Virus Interactions. For example, one-third of patients with EBV+ NK/T-cell lymphoma carried two novel nonsense variants (Q322X, G342X) of LMP1 and both variant proteins failed to restrict viral reactivation, confirming loss of virostatic function. 2019 Cancer research Abstract EBV Q322X;G342X 101;108 106;113 LMP1 118 122 NK/T-cell lymphoma 45 63 32847853 Epstein-Barr Virus gH/gL and Kaposi's Sarcoma-Associated Herpesvirus gH/gL Bind to Different Sites on EphA2 To Trigger Fusion. In addition, the mutations located in the large groove of EBV gH/gL (R152A and G49C) also have decreased binding with EphA2. 2020 Journal of virology Abstract EBV R152A;G49C 69;79 74;83 gH;gL 62;65 64;67 32847853 Epstein-Barr Virus gH/gL and Kaposi's Sarcoma-Associated Herpesvirus gH/gL Bind to Different Sites on EphA2 To Trigger Fusion. To determine whether this glycosylation site may be the binding region for EphA2, we compared the EphA2 binding activity of EBV gH/gL and the EBV gH/gL-N69L/S71V mutant. 2020 Journal of virology Abstract EBV N69L;S71V 152;157 156;161 gH;gH;gL;gL 128;146;131;149 130;148;133;151 32847853 Epstein-Barr Virus gH/gL and Kaposi's Sarcoma-Associated Herpesvirus gH/gL Bind to Different Sites on EphA2 To Trigger Fusion. We found that EBV gH/gL-N69L/S71V had higher binding affinity for EphA2, indicating that the EBV gL N-glycosylation site might be responsible for inhibiting the binding of gH/gL to EphA2. 2020 Journal of virology Abstract EBV N69L;S71V 24;29 28;33 gH;gH;gL;gL;gL 18;172;21;175;97 20;174;23;177;99 32847853 Epstein-Barr Virus gH/gL and Kaposi's Sarcoma-Associated Herpesvirus gH/gL Bind to Different Sites on EphA2 To Trigger Fusion. We previously identified that an EBV gL N-glycosylation mutant (gL-N69L/S71V) was hyperfusogenic in epithelial cells but not in B cells. 2020 Journal of virology Abstract EBV N69L;S71V 67;72 71;76 gL;gL 37;64 39;66 33242451 Analysis of latent T-cell epitopes in Epstein-Barr virus isolated from extranodal nasal-type natural killer/T-cell lymphoma in Taiwanese population. Additionally, the AVFDRKSDAK (A1S/P and V2F/M/L) and YHLIVDTDSL (I4L and L10R/V/G/H) epitopes were associated with 5 patterns of amino acid changes in EBNA3B and EBNA-2, respectively. 2021 Experimental and molecular pathology Abstract EBV A1S;A1P;V2F;V2M;V2L;I4L;L10R;L10V;L10G;L10H 30;30;40;40;40;65;73;73;73;73 35;35;47;47;47;68;83;83;83;83 EBNA2;EBNA3B 162;151 168;157 33633271 The influence of human genetic variation on Epstein-Barr virus sequence diversity. Three polymorphic regions in the human genome were found to be associated with EBV variation: one at the amino acid level (BRLF1:p.Lys316Glu); and two at the gene level (burden testing of rare variants in BALF5 and BBRF1). 2021 Scientific reports Abstract EBV K316E 129 140 BALF5;BBRF1;BRLF1 205;215;123 210;220;128 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. In particular, the two arginine substitution, R521A and R522A, significantly affected the total binding energy. 2021 Frontiers in molecular biosciences Abstract EBV R521A;R522A 46;56 51;61 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. Our analysis revealed that R469A, K514A, Y518A, R521A and R522A are the key hotspots for the recognition of dsDNA by the EBNA1. 2021 Frontiers in molecular biosciences Abstract EBV R469A;K514A;Y518A;R521A;R522A 27;34;41;48;58 32;39;46;53;63 EBNA1 121 126 34304093 Characterization of a cancer-associated Epstein-Barr virus EBNA1 variant reveals a novel interaction with PLOD1 and PLOD3. Here we show that, while these mutations do not impact EBNA1 plasmid maintenance function, one of them (Thr85Ala) decreases transcriptional activation and results in a gain of function interaction with PLOD1 and PLOD3. 2021 Virology Abstract EBV T85A 104 112 EBNA1 55 60 34567789 A comprehensive analysis of genetic diversity of EBV reveals potential high-risk subtypes associated with nasopharyngeal carcinoma in China. The newly identified EBV subtypes, which contains four Chinese-specific NPC-associated amino acid substitutions (BALF2 V317M, BNRF1 G696R, V1222I and RPMS1 D51E), showed a robust positive association with the risk of NPC in China (Odds Ratio = 4.80, 20.00, 18.24 and 32.00 for 1, 2, 3 and 4 substitutions, respectively, P trend <0.001). 2021 Virus evolution Abstract EBV V317M;G696R;V1222I;D51E 119;132;139;156 124;137;145;160 BNRF1;RPMS1;BALF2 126;150;113 131;155;118 Nasopharyngeal carcinoma;Nasopharyngeal carcinoma 217;72 220;75 8234266 Serine-173 of the Epstein-Barr virus ZEBRA protein is required for DNA binding and is a target for casein kinase II phosphorylation. S173 is a functional component of ZEBRA's DNA binding domain, since mutation of S173 to alanine (S173A) reduced DNA binding in vitro to 10% of wild-type levels. 1993 Proc Natl Acad Sci U S A Abstract EBV S173A;S173A 80;97 95;102 BZLF1 34 39 8234266 Serine-173 of the Epstein-Barr virus ZEBRA protein is required for DNA binding and is a target for casein kinase II phosphorylation. Transcriptional activation of a native viral promoter in vivo by mutant S173A was also reduced markedly. 1993 Proc Natl Acad Sci U S A Abstract EBV S173A 72 77 9060666 Alteration of a single serine in the basic domain of the Epstein-Barr virus ZEBRA protein separates its functions of transcriptional activation and disruption of latency. Therefore, initiation of the EBV lytic cycle by the ZEBRA protein requires a function in addition to transcriptional activation; a change of serine 186 to alanine in the DNA-binding domain of ZEBRA abolished this additional function and uncovered a new role for the ZEBRA protein in disruption of EBV latency. 1997 Journal of virology Abstract EBV S186A 141 162 BZLF1;BZLF1;BZLF1 52;192;266 57;197;271 9060666 Alteration of a single serine in the basic domain of the Epstein-Barr virus ZEBRA protein separates its functions of transcriptional activation and disruption of latency. We generated a point mutant of ZEBRA, Z(S186A), that was not impaired in its ability to activate transcription; however, this mutation abolished its ability to initiate the viral lytic cascade. 1997 Journal of virology Abstract EBV S186A 40 45 BZLF1;BZLF1 31;38 36;39 9123876 The bZip dimerization domain of the Epstein-Barr virus BZLF1 (Z) protein mediates lymphoid-specific negative regulation. In lymphoid cells, a Z mutant which has been altered at amino acid 200 (tyrosine to glutamic acid) transactivates both the early BMRF1 promoter and the immediate-early BZLF1 promoter (Zp) four- to fivefold better than wild-type Z. 1997 Virology Abstract EBV Y200E 67 98 BMRF1;BZLF1;BZLF1;BZLF1;BZLF1 129;168;21;228;184 134;173;22;229;186 9466647 Amino-acid change in the Epstein-Barr-virus ZEBRA protein in undifferentiated nasopharyngeal carcinomas from Europe and North Africa. We found that an alanine 206 had been replaced by a serine in the Z95 sequence in 72% of the NPC biopsies from European and North African patients. 1998 International journal of cancer Abstract EBV A206S 17 58 Nasopharyngeal carcinoma 93 96 9501034 Distinct regions of EBV DNase are required for nuclease and DNA binding activities. Mutation of Leu23 to Gly showed drastically reduced nuclease activity but its DNA binding ability was not affected. 1998 Virology Abstract EBV L23G 12 24 9733827 Role of the TRAF binding site and NF-kappaB activation in Epstein-Barr virus latent membrane protein 1-induced cell gene expression. In contrast, LMP1(P204A/Q206A) was substantially more impaired in TRAF1, EBI3, and EGF-R induction. 1998 Journal of virology Abstract EBV P204A;Q206A 18;24 23;29 LMP1 13 17 9733827 Role of the TRAF binding site and NF-kappaB activation in Epstein-Barr virus latent membrane protein 1-induced cell gene expression. This mutant, LMP1(P204A/Q206A), induced 60% of wild-type LMP1 NF-kappaB activation and had approximately 60% of wild-type LMP1 effect on Fas, ICAM-1, CD40, and LFA-3 induction. 1998 Journal of virology Abstract EBV P204A;Q206A 18;24 23;29 LMP1;LMP1;LMP1 13;57;122 17;61;126 9813214 Rescue of the Epstein-Barr virus BZLF1 mutant, Z(S186A), early gene activation defect by the BRLF1 gene product. Furthermore, we demonstrate that the ability of Z(S186A) to induce early BMRF1 and BHRF1 gene expression is rescued by cotransfection with a BRLF1 expression vector. 1998 Virology Abstract EBV S186A 50 55 BHRF1;BMRF1;BRLF1;BZLF1 83;73;141;48 88;78;146;49 9813214 Rescue of the Epstein-Barr virus BZLF1 mutant, Z(S186A), early gene activation defect by the BRLF1 gene product. However, the Z(S186A)/BRLF1 (R) combination cannot induce full lytic replication, suggesting that Z(S186A) may also be deficient in a replication-specific function. 1998 Virology Abstract EBV S186A;S186A 15;100 20;105 BRLF1;BZLF1;BZLF1 22;13;98 27;14;99 9813214 Rescue of the Epstein-Barr virus BZLF1 mutant, Z(S186A), early gene activation defect by the BRLF1 gene product. Recently, a serine-to-alanine mutation of Z residue 186 (within the basic DNA binding domain) was shown to inhibit the ability of Z to induce lytic infection in latently infected cells, although the Z(S186A) mutant could still bind several known ZREs and activated an early EBV promoter (BMRF1) in transient reporter gene assays (Francis, A.) 1998 Virology Abstract EBV S186A 201 206 BMRF1;BZLF1;BZLF1;BZLF1 288;42;130;199 293;43;131;200 9813214 Rescue of the Epstein-Barr virus BZLF1 mutant, Z(S186A), early gene activation defect by the BRLF1 gene product. We now show that a specific deficiency in the ability to bind to ZRE elements in the immediate-early BRLF1 promoter may account for the inability of Z(S186A) to activate BRLF1 expression. 1998 Virology Abstract EBV S186A 151 156 BRLF1;BRLF1;BZLF1 101;170;149 106;175;150 18369464 Methylated DNA recognition during the reversal of epigenetic silencing is regulated by cysteine and serine residues in the Epstein-Barr virus lytic switch protein. A previous study had shown that the point mutation S186A compromises Zta's ability to bind both the methylated and non-methylated forms of the ZREs within Rp. 2008 PLoS pathogens Introduction EBV S186A 51 56 BZLF1 69 72 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. F600A/ F605A mutations not only weakened the transactivation activity of intact Rta protein, they also decreased the transactivation function of GAL4-Rta fusion proteins. 2009 Virology Introduction EBV F600A;F605A 0;7 5;12 BRLF1;BRLF1 80;150 83;153 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. F600A/F605A mutations overcame the action of the DBIS. 2009 Virology Introduction EBV F600A;F605A 0;6 5;11 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. The F600A/ F605A mutations not only enhanced binding by Rta they significantly decreased the transactivation function of Rta in several different biologic assays for activation of EBV lytic gene expression. 2009 Virology Introduction EBV F600A;F605A 4;11 9;16 BRLF1;BRLF1 56;121 59;124 19325883 Methylation-dependent binding of the epstein-barr virus BZLF1 protein to viral promoters. We also demonstrate that the CpG motifs in the Nap ZREs are usually methylated on the EBV genome during latent infection, and that a Z mutant, Z(S186A), which cannot bind to the methylated Nap ZREs in vitro is unable to activate Na expression in latently infected cells. 2009 PLoS pathogens Introduction EBV S186A 145 150 BZLF1;BZLF1 133;143 134;144 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. Additional proof for the role of phosphorylation of S173 in replication was attained when a phosphomimetic substitution mutant Z(S173D) activated both transcription and replication and was competent to bind DNA to the same extent as wild-type (wt) ZEBRA. 2010 PLoS pathogens Introduction EBV S173D 129 134 BZLF1;BZLF1 248;127 253;128 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. In addition, the S173A mutant demonstrates that activation of transcription is not sufficient to stimulate viral replication. 2010 PLoS pathogens Introduction EBV S173A 17 22 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. Two of these mutants, Z(Y180E) and Z(K188A), caused lytic cycle arrest prior to viral replication. 2010 PLoS pathogens Introduction EBV Y180E;K188A 24;37 29;42 BZLF1;BZLF1 22;35 23;36 26337172 Sequence analysis of Epstein-Barr virus (EBV) early genes BARF1 and BHRF1 in NK/T cell lymphoma from Northern China. V29A strains, a BARF1 mutant subtype, showed higher prevalence in NPC, which may suggest the association between this variation and NPC. 2015 Virology journal Introduction EBV V29A 0 4 BARF1 16 21 Nasopharyngeal carcinoma;Nasopharyngeal carcinoma 66;132 69;135 26675171 A single nucleotide polymorphism in the Epstein-Barr virus genome is strongly associated with a high risk of nasopharyngeal carcinoma. The most striking finding is that a single nucleotide polymorphism (SNP) in the EBV-encoded RPMS1 gene (locus 155391: G>A, named G155391A) is significantly associated with NPC incidence. 2015 Chinese journal of cancer Introduction EBV G155391A 129 137 RPMS1 92 97 Nasopharyngeal carcinoma 172 175 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. A recent X-ray structure of mutant Zta(C189S) binding meZRE2 highlights how the methyl group on 5mC is similar to the analogous methyl group in thymine. 2018 Biochemical and biophysical research communications Introduction EBV C189S 39 44 BZLF1 35 38 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. Additionally, the consequence of changing Zta to Zta(C189S) on binding other DNA sequences has not been determined. 2018 Biochemical and biophysical research communications Introduction EBV C189S 53 58 BZLF1;BZLF1 42;49 45;52 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. C189S mutants retain sequence-specificity in binding to several sequences, such as the meZRE2, oriLyt (TGTGTAA), and to the meTRE and TRE motifs. 2018 Biochemical and biophysical research communications Introduction EBV C189S 0 5 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. However, it is unclear whether this replication defect in Zta(C189S) mutants is due to altered DNA binding specificity, which may be possible as amino acids in position 189 are in close proximity to the phosphate 5' of thymines (T-4) in the meZRE2 and TRE motifs. 2018 Biochemical and biophysical research communications Introduction EBV C189S 62 67 BZLF1 58 61 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. In this study, we examine the DNA binding specificity of four mutations of Zta(C189) - C189S, C189T, C189A, and C189V - to four types of dsDNA using PBMs. 2018 Biochemical and biophysical research communications Introduction EBV C189S;C189T;C189A;C189V 87;94;101;112 92;99;106;117 BZLF1 75 78 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. One report indicates Zta(C189S) loses binding specificity to methylated DNA sequences critical for in vivo function, such as meZRE2 and meZRE3 (TTMGMGA). 2018 Biochemical and biophysical research communications Introduction EBV C189S 25 30 BZLF1 21 24 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. Van der Waals interactions between the beta carbon of S189 in Zta(C189S) with T-4 of both the TRE and meZRE2, and with methylated cytosine (M-3) of the opposite strand of meZRE2 are also possible. 2018 Biochemical and biophysical research communications Introduction EBV C189S 66 71 BZLF1 62 65 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. Zta(C189S) results in a virus that is defective in DNA replication and is unable to execute the virus lytic cycle. 2018 Biochemical and biophysical research communications Introduction EBV C189S 4 9 BZLF1 0 3 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. Additionally, other studies also reported that K514A also reduces the binding affinity significantly. 2021 Frontiers in molecular biosciences Introduction EBV K514A 47 52 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. At the same time, others reported that three residues R491E, R491A, and D581E significantly impair the DNA binding. 2021 Frontiers in molecular biosciences Introduction EBV R491E;R491A;D581E 54;61;72 59;66;77 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. Previous studies determining the dissociation constant (KD) for the EBNA1-DNA association reported that mutating interacting residues, R469A reduced the binding of DNA by 300-fold, Y518A by 80-fold and R522A by 1600-fold. 2021 Frontiers in molecular biosciences Introduction EBV R469A;Y518A;R522A 135;181;202 140;186;207 EBNA1 68 73 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. pRTS, pRTS/Rta, RpCAT (-299/+58), BMLF1(RRE)/CAT and CMV/Z(S186A) have been described. 2009 Virology Method EBV S186A 59 64 BMLF1;BRLF1 34;11 39;14 19325883 Methylation-dependent binding of the epstein-barr virus BZLF1 protein to viral promoters. Structures of Z bound to four different ZREs were modeled based on the crystal structure of Z (S186A, C189S) bound to the AP1 site (PDB code: 2c9l) using the Sybyl program. 2009 PLoS pathogens Method EBV S186A;C189S 95;102 100;107 BZLF1;BZLF1 14;92 15;93 19325883 Methylation-dependent binding of the epstein-barr virus BZLF1 protein to viral promoters. Z(S186A) and Z(C189S) mutations in the pSG5-ZcDNA vector were constructed using the QuikChange site-directed mutagenesis kit (Stratagene) to allow in vitro translation of the mutant proteins. 2009 PLoS pathogens Method EBV S186A;C189S 2;15 7;20 BZLF1;BZLF1 0;13 1;14 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. The plasmids pHD1013/Z, pHD1013/Z(S173A), pHD1013/Z(R187K), pHD1013/Z(Y180E), pHD1013/Z(K188A), pHD1013/Z(K188R), pHD1013/Z(F193E) and pHD1013/Z(K194A) were prepared as described previously. 2010 PLoS pathogens Method EBV S173A;R187K;Y180E;K188A;K188R;F193E;K194A 34;52;70;88;106;124;145 39;57;75;93;111;129;150 BZLF1;BZLF1;BZLF1;BZLF1;BZLF1;BZLF1;BZLF1;BZLF1 21;32;50;68;86;104;122;143 22;33;51;69;87;105;123;144 21440926 Epstein-Barr virus nuclear protein 3C binds to the N-terminal (NTD) and beta trefoil domains (BTD) of RBP/CSL; only the NTD interaction is essential for lymphoblastoid cell growth. Briefly, 7.5 x 106 EBNA3C-HT infected LCLs were transfected with 15 mug of oriP plasmid DNA expressing E3C, E3C W227S mutant, or control GFP oriP plasmid. 2011 Virology Method EBV W227S 112 117 EBNA3C 19 25 21440926 Epstein-Barr virus nuclear protein 3C binds to the N-terminal (NTD) and beta trefoil domains (BTD) of RBP/CSL; only the NTD interaction is essential for lymphoblastoid cell growth. EBNA3C W227S was generated by Quickchange PCR (Stratagene, La Jolla, CA) and the mutated fragment cloned into the GST, pSG5-Flag and pCep EBNA3C wild-type plasmids to generate appropriate point mutants. 2011 Virology Method EBV W227S 7 12 EBNA3C;EBNA3C 0;138 6;144 21560118 Transmembrane peptides used to investigate the homo-oligomeric interface and binding hotspot of latent membrane protein 1. pRSV-LMP-1-D150A was generated using site-directed mutagenesis (Agilent Technologies 210519, CA, USA) to substitute D150 to alanine with the forward primer 5'-CCTAGCCTTCTTCCTAGCCCTCATCCTGCTC-3' and its reverse complement. 2011 Biopolymers Method EBV D150A 10 16 LMP1 5 10 21560118 Transmembrane peptides used to investigate the homo-oligomeric interface and binding hotspot of latent membrane protein 1. pTox7 TM5 D150A was created using standard site directed mutagenesis with a commercially available Stratagene Quikchange II kit (Agilent, CA, USA). 2011 Biopolymers Method EBV D150A 10 15 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. The strength of the association between the two sets of polymorphisms I124V/I152L and F144I/I150A/L151I and the etiology of HL was tested with a simple logistic regression and then with a logistic regression model controlling for sex, age, CD4 levels and the number of years of antiretroviral therapy at the date of blood sampling, using Stata 11 software (StataCorp, http://www.stata.com). 2012 PloS one Method EBV I124V;I152L;F144I;I150A;L151I 70;76;86;92;98 75;81;91;97;103 Hodgkin lymphoma 124 126 24016332 Identification of a novel variant of LMP-1 of EBV in patients with endemic Burkitt lymphoma in western Kenya. Plasmids containing cloned LMP-1 PCR products were sent to Genewiz (South Plainfield, NJ, USA) for sequencing using M13R universal primers. 2013 Infectious agents and cancer Method EBV M13R 116 120 LMP1 27 32 24075898 High molecular weight complex analysis of Epstein-Barr virus Latent Membrane Protein 1 (LMP-1): structural insights into LMP-1's homo-oligomerization and lipid raft association. The following cysteine substitution mutants are all constructed in the pCMV-LMP-1 background: pCMV-LMP-1/CsubA1 has an alanine codon in place of cysteine 78 (C78A); pCMV-LMP-1/CsubA1,2 has alanine codons in place of cysteines 78 and 84 (C78A; C84A); pCMV-LMP-1/CsubA3 has an alanine in place of cysteine 116 (C116A); pCMV-LMP-1/CsubA1-3 has alanine codons in place of cysteines 78, 84, and 116 (C78A; C84A; C116A); pCMV-LMP-1/CsubA4 has an alanine codon in place of cysteine 238 (C238A); pCMV-LMP-1/CsubA1-4 has alanine codons in place of cysteines 78, 84, 116, and 238 (C78CA; C84A; C116A; C238A). 2013 Virus research Method EBV C78A;C78A;C84A;C116A;C78A;C84A;C116A;C238A;C84A;C116A;C238A;C78A;C116A;C238A 158;237;243;309;395;401;407;480;578;584;591;119;275;440 162;241;247;314;399;405;412;485;582;589;596;156;307;478 LMP1;LMP1;LMP1;LMP1;LMP1;LMP1;LMP1 76;99;170;255;322;420;493 81;104;175;260;327;425;498 25865256 Exosomal sorting of the viral oncoprotein LMP1 is restrained by TRAF2 association at signalling endosomes. HEK293 cells were transfected as described above with pGK2-LMP1wt or pGK2LMP1-C78A or pEGFP-N1. 2015 Journal of extracellular vesicles Method EBV C78A 77 82 25865256 Exosomal sorting of the viral oncoprotein LMP1 is restrained by TRAF2 association at signalling endosomes. pGK2-LMP1-C78A was constructed by targeted mutagenesis of pGK2-LMP1wt, using the QuikChange Lightning Site-Directed Mutagenesis Kit protocol (Agilent, Santa Clara, CA, USA) and 5'-TTCAGAAGAGACCTTCTCGCTCCACTTGGAGCCCTTTG-3' as primer. 2015 Journal of extracellular vesicles Method EBV C78A 9 14 LMP1 5 9 25950714 DNA Damage Signaling Is Induced in the Absence of Epstein-Barr Virus (EBV) Lytic DNA Replication and in Response to Expression of ZEBRA. After 8 h the transfection reagent was replaced with growth media and cells were incubated for another 24 hours.The lentivirus construct P3465V was kindly provided by Bill Sugden. 2015 PloS one Method EBV P3465V 137 143 25950714 DNA Damage Signaling Is Induced in the Absence of Epstein-Barr Virus (EBV) Lytic DNA Replication and in Response to Expression of ZEBRA. PCR fragments were digested with BamH1 and EcoRI and ligated into the P3465V construct digested with BamH1 and EcoRI. 2015 PloS one Method EBV P3465V 70 76 25950714 DNA Damage Signaling Is Induced in the Absence of Epstein-Barr Virus (EBV) Lytic DNA Replication and in Response to Expression of ZEBRA. The plasmids pHD1013/Z, pHD1013/Z(S186A), pHD1013/Z(S186E), pHD1013/Z(R179A), pHD1013/Z(R183E), pHD1013/Z(N182E) were described previously. 2015 PloS one Method EBV S186A;S186E;R179A;R183E;N182E 34;52;70;88;106 39;57;75;93;111 BZLF1;BZLF1;BZLF1;BZLF1;BZLF1;BZLF1 21;32;50;68;86;104 22;33;51;69;87;105 27009860 ERK2 phosphorylation of EBNA1 serine 383 residue is important for EBNA1-dependent transactivation. Cytoplasmic and nuclear proteins from BJ-FE1 S383 WT, and S383A MT cells treated with DMSO and U0126 for 3 days were washed in 1 mL of ice cold PBS and then fractionated. 2016 Oncotarget Method EBV S383A 58 63 27009860 ERK2 phosphorylation of EBNA1 serine 383 residue is important for EBNA1-dependent transactivation. Different EBNA1 constructs (387-641 WT, 379-~641 WT, or MTs of S383A, I528S, T582F, PAS (DM), and AAGTAPAS (QM)) were tagged with 6x histidine at the N-terminus and purified from Escherichia coli BL21 (DE3) Rosetta/pLysS cells as described previously. 2016 Oncotarget Method EBV S383A;I528S;T582F 63;70;77 68;75;82 EBNA1 10 15 27009860 ERK2 phosphorylation of EBNA1 serine 383 residue is important for EBNA1-dependent transactivation. EBNA1 mutants S383A, PAS (double mutation; DM), AAGTAPAS (quadruple mutation; QM) were generated using Quick Change (Stratagene, La Jolla, CA). 2016 Oncotarget Method EBV S383A 14 19 EBNA1 0 5 27009860 ERK2 phosphorylation of EBNA1 serine 383 residue is important for EBNA1-dependent transactivation. FE1_S383 (131 glycine-alanine repeats), S383A (131 GA), S383D (<123 GA), I528S (~133GA), DM (~133 GA), and QM (131 GA) were generated using a full length FE1 WT S383 template with all 235 GA repeats. 2016 Oncotarget Method EBV S383A;S383D;I528S;G131A 40;56;73;10 45;61;78;29 27009860 ERK2 phosphorylation of EBNA1 serine 383 residue is important for EBNA1-dependent transactivation. In addition, EGFP-EBNA1 S383A was made using EGFP-EBNA1 as template. 2016 Oncotarget Method EBV S383A 24 29 EBNA1;EBNA1 18;50 23;55 27009860 ERK2 phosphorylation of EBNA1 serine 383 residue is important for EBNA1-dependent transactivation. Subcellular localization of EGFP-EBNA1 S383 WT and S383A MT in BJAB cells was assayed by live confocal microscopy as described previously. 2016 Oncotarget Method EBV S383A 51 56 EBNA1 33 38 29221111 Nasopharyngeal carcinoma risk prediction via salivary detection of host and Epstein-Barr virus genetic variants. The most striking finding was a significant association between a single nucleotide polymorphism (SNP) in the EBV-encoded RPMS1 gene (locus 155391: G > A, referred to here as G155391A, resulting in the alternation of Asp to Asn) and NPC risk. 2017 Oncotarget Method EBV G155391A 175 183 RPMS1 122 127 Nasopharyngeal carcinoma 233 236 29221111 Nasopharyngeal carcinoma risk prediction via salivary detection of host and Epstein-Barr virus genetic variants. Thus, G155391A in RPMS1 of EBV may represent a specific EBV variant in the NPC-endemic region of southern China that could serve as an indicator of high risk of NPC in this population. 2017 Oncotarget Method EBV G155391A 6 14 RPMS1 18 23 Nasopharyngeal carcinoma;Nasopharyngeal carcinoma 161;75 164;78 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. Mutant constructs of Zta (C189S, C189T, C189V, and C189A) were generated via site-directed mutagenesis of the wild-type construct (GenScript). 2018 Biochemical and biophysical research communications Method EBV C189S;C189T;C189V;C189A 26;33;40;51 31;38;45;56 BZLF1 21 24 34567789 A comprehensive analysis of genetic diversity of EBV reveals potential high-risk subtypes associated with nasopharyngeal carcinoma in China. In the present study, a novel mutation (BNRF1 V1222I, loc5399) was validated via nested PCR and Sanger sequencing using mouthwashes from 108 NPC cases and 179 controls in our EPI-NPC-2005 project. 2021 Virus evolution Method EBV V1222I 46 52 BNRF1 40 45 Nasopharyngeal carcinoma;Nasopharyngeal carcinoma 141;179 144;182 18369464 Methylated DNA recognition during the reversal of epigenetic silencing is regulated by cysteine and serine residues in the Epstein-Barr virus lytic switch protein. An independent mutation of C189 to alanine (ZtaC189A) also resulted in decreased binding to meZRE3, suggesting that the decreased binding of the C189S mutant was due to loss of the cysteine and not, for example, merely due to phosphorylation of the newly introduced serine. 2008 PLoS pathogens Result EBV C189S 145 150 BZLF1 44 47 18369464 Methylated DNA recognition during the reversal of epigenetic silencing is regulated by cysteine and serine residues in the Epstein-Barr virus lytic switch protein. As shown in Figure 8C, ZtaS186A binds more weakly to meZRE2 than does wild type Zta, in agreement with previous studies; omitting the cytosine-2 methyl group further decreases the relative binding affinity, consistent with the loss of an important contact. 2008 PLoS pathogens Result EBV S186A 26 31 BZLF1;BZLF1 23;80 26;83 18369464 Methylated DNA recognition during the reversal of epigenetic silencing is regulated by cysteine and serine residues in the Epstein-Barr virus lytic switch protein. Moreover, the absence of this thiol-methyl contact in non-methylated ZRE sites explains why the C189S mutation has little effect on the binding to non-methylated ZRE2 (Figure 2D). 2008 PLoS pathogens Result EBV C189S 96 101 18369464 Methylated DNA recognition during the reversal of epigenetic silencing is regulated by cysteine and serine residues in the Epstein-Barr virus lytic switch protein. On the contrary, binding is comparable to that of the wild type, which is dramatically reduced compared to binding to the fully methylated ZRE3; the methyl group of cytosine-2 enhances the DNA binding affinity of wild type Zta to a greater extent than that of the C189S mutant. 2008 PLoS pathogens Result EBV C189S 264 269 BZLF1 223 226 18369464 Methylated DNA recognition during the reversal of epigenetic silencing is regulated by cysteine and serine residues in the Epstein-Barr virus lytic switch protein. Our model predicts that omitting this group should more significantly compromise the binding affinity (relative to wild type) of the S186A mutant over that of the C189S mutant, because only the former conserves the cysteine thiol group. 2008 PLoS pathogens Result EBV S186A;C189S 133;163 138;168 18369464 Methylated DNA recognition during the reversal of epigenetic silencing is regulated by cysteine and serine residues in the Epstein-Barr virus lytic switch protein. This interaction is symmetrically equivalent to that of C189Left with the cytosine-2 methyl group and consequently should also be destabilized by the C189S mutation (Figure 6D). 2008 PLoS pathogens Result EBV C189S 150 155 18369464 Methylated DNA recognition during the reversal of epigenetic silencing is regulated by cysteine and serine residues in the Epstein-Barr virus lytic switch protein. This is in stark contrast with the results observed for ZtaC189S: although the relative affinity of this mutant toward meZRE3 is weak, it is not significantly further reduced upon omitting the cytosine-2 methyl group (Figure 8D). 2008 PLoS pathogens Result EBV C189S 59 64 BZLF1 56 59 18369464 Methylated DNA recognition during the reversal of epigenetic silencing is regulated by cysteine and serine residues in the Epstein-Barr virus lytic switch protein. Thus, the prediction is that the C189S mutation destabilizes contacts in both half-sites of meZRE3, but in only one of ZRE2. 2008 PLoS pathogens Result EBV C189S 33 38 18369464 Methylated DNA recognition during the reversal of epigenetic silencing is regulated by cysteine and serine residues in the Epstein-Barr virus lytic switch protein. We next investigated the contribution of the cytosine-2 methyl group to the binding affinity of the S186A and C189S point mutants. 2008 PLoS pathogens Result EBV S186A;C189S 100;110 105;115 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. 2089 cells co-transfected with S186A and Rta-expression plasmids were stained for ZEBRA and EA-D, as a marker for Rta activity. 2008 Virology Result EBV S186A 31 36 BZLF1;BMRF1;BRLF1;BRLF1 82;92;41;114 87;96;44;117 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. 3: panels xv, xviii) in a significant proportion of ZEBRA-positive cells, producing a ZEBRA distribution remarkably similar to the pattern observed with mutant R179A. 2008 Virology Result EBV R179A 160 165 BZLF1;BZLF1 52;86 57;91 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. 7, panel xii) into 2089 cells resulted in a discrete punctate distribution of ZEBRA similar to that seen with the R179A and Y180E mutants. 2008 Virology Result EBV R179A;Y180E 114;124 119;129 BZLF1 78 83 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. A novel pattern of EA-D and ZEBRA distribution, never observed in the 293 cell/EBV bacmid system, was also seen in some EA-D-positive D98/HR-1 cells after transfection of the R179A mutant. 2008 Virology Result EBV R179A 175 180 BZLF1;BMRF1;BMRF1 28;19;120 33;23;124 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. Another subpopulation of D98/HR-1 cells transfected with R179A ZEBRA stained positively for EA-D protein and for ZEBRA. 2008 Virology Result EBV R179A 57 62 BZLF1;BZLF1;BMRF1 63;113;92 68;118;96 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. As seen in wild-type ZEBRA-transfected cells, the diffuse K188R ZEBRA staining was often slightly, yet unmistakably, increased in areas co-localizing with globular replication compartments. 2008 Virology Result EBV K188R 58 63 BZLF1;BZLF1 21;64 26;69 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. Because the R179A mutant itself is incapable of activating BMRF1 expression in cells containing EBV-bacmids, the presence of BMRF1-positive cells following transfection of R179A ZEBRA into D98/HR-1 cells suggests that the R179A mutant auto-stimulates the endogenous wild-type BZLF1 gene in this cell background. 2008 Virology Result EBV R179A;R179A;R179A 12;172;222 17;177;227 BMRF1;BMRF1;BZLF1;BZLF1 59;125;276;178 64;130;281;183 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. Both mutants bind ZIIIB DNA relatively weakly; K181A binds 37% and A185V 10% as actively as wild-type. 2008 Virology Result EBV K181A;A185V 47;67 52;72 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. Both mutations completely abolish ZEBRA's capacity to disrupt latency; however, the S186A mutant retains its capacity to bind ZIIIB DNA, whereas S186E does not bind ZIIIB DNA. 2008 Virology Result EBV S186A;S186E 84;145 89;150 BZLF1 34 39 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. Cells co-transfected with S186A and Rta showed bright EA-D staining, indicating that Rta was active. 2008 Virology Result EBV S186A 26 31 BMRF1;BRLF1;BRLF1 54;36;85 58;39;88 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. Cells expressing Z(S186A) never contained EA-D. 2008 Virology Result EBV S186A 19 24 BMRF1;BZLF1 42;17 46;18 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. Cells of this type seemed to exhibit a mixture of both the discrete punctate R179A mutant phenotype and the wild-type ZEBRA phenotype. 2008 Virology Result EBV R179A 77 82 BZLF1 118 123 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. Consistent with previous immunoblot experiments, Y180E ZEBRA induced high levels of EA-D expression (; Fig 4.). 2008 Virology Result EBV Y180E 49 54 BZLF1;BMRF1 55;84 60;88 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. D98/HR-1 cells transfected with R179A ZEBRA showed a spectrum of nuclear morphological characteristics. 2008 Virology Result EBV R179A 32 37 BZLF1 38 43 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. EA-D staining in K188R-transfected cells was also indistinguishable from wild-type ZEBRA induced cells. 2008 Virology Result EBV K188R 17 22 BZLF1;BMRF1 83;0 88;4 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. Effect of viral DNA replication inhibitors, phosphonoacetic acid (PAA) and acyclovir (ACV), on localization of ZEBRA and EA-D in cells transfected with wild-type or R179A mutant ZEBRA. 2008 Virology Result EBV R179A 165 170 BZLF1;BZLF1;BMRF1 111;178;121 116;183;125 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. Exogenous expression of Rta did not affect the distribution of S186A mutant ZEBRA which remained diffusely and smoothly distributed throughout the intranuclear space. 2008 Virology Result EBV S186A 63 68 BZLF1;BRLF1 76;24 81;27 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. However, unlike EA-D staining induced by wild-type ZEBRA, EA-D induced by Y180E was distributed diffusely throughout the nucleus in nearly all cells positive for EA-D. 2008 Virology Result EBV Y180E 74 79 BZLF1;BMRF1;BMRF1;BMRF1 51;16;58;162 56;20;62;166 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. However, unlike wild-type ZEBRA, the S186A mutant protein was never observed in globular areas of increased ZEBRA staining. 2008 Virology Result EBV S186A 37 42 BZLF1;BZLF1 26;108 31;113 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. Immunofluorescence analysis of BZKO and 2089 cells transfected with the K188R mutant showed distributions of ZEBRA and EA-D protein which were indistinguishable from cells transfected with wild-type ZEBRA. 2008 Virology Result EBV K188R 72 77 BZLF1;BZLF1;BMRF1 109;199;119 114;204;123 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. In 2089 cells transfected with Y180E, a small percentage, approximately 3% (4 of 142 cells selected at random), of cells positive for EA-D showed mature viral replication compartments, compared to approximately 28% (40 of 145 cells) of 2089 cells transfected with wild-type ZEBRA. 2008 Virology Result EBV Y180E 31 36 BZLF1;BMRF1 274;134 279;138 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. In BZKO and 2089 cells the appearance of the ZEBRA early mutant, R179A, was dramatically different than wild-type and S186A mutant ZEBRA. 2008 Virology Result EBV R179A;S186A 65;118 70;123 BZLF1;BZLF1 45;131 50;136 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. In the nuclei of 293 cells, R179A and Y180E mutant ZEBRA proteins were distributed non-uniformly. 2008 Virology Result EBV R179A;Y180E 28;38 33;43 BZLF1 51 56 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. In this subpopulation of D98/HR-1 cells the phenotype of R179A mutant ZEBRA resembled the phenotype seen in BZKO and 2089 cells. 2008 Virology Result EBV R179A 57 62 BZLF1 70 75 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. Instead of the diffuse distribution of wild-type and S186A ZEBRA, the R179A mutant localized to numerous small discrete punctate foci within the nuclei. 2008 Virology Result EBV S186A;R179A 53;70 58;75 BZLF1 59 64 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. Intranuclear distribution of S186A mutant ZEBRA is not affected by exogenous expression of Rta. 2008 Virology Result EBV S186A 29 34 BZLF1;BRLF1 42;91 47;94 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. Intranuclear distribution of wild-type and R179A mutant ZEBRA in D98/HR-1 cells. 2008 Virology Result EBV R179A 43 48 BZLF1 56 61 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. K181A activates low levels of Rta and A185V activates only trace levels of the protein. 2008 Virology Result EBV K181A;A185V 0;38 5;43 BRLF1 30 33 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. Moreover, since R179A does not activate BMRF1, the results show that discrete punctate foci of ZEBRA are generated independently of the presence of the viral polymerase processivity factor. 2008 Virology Result EBV R179A 16 21 BMRF1;BZLF1 40;95 45;100 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. Mutation of the tyrosine at position 180 to glutamate therefore, allows EA-D expression but prevents the formation of replication compartments. 2008 Virology Result EBV Y180E 16 53 BMRF1 72 76 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. No EA-D protein was seen in cells expressing the R179A mutant. 2008 Virology Result EBV R179A 49 54 BMRF1 3 7 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. One possible reason for the different distribution pattern of S186A, as compared with the R179A and Y180E mutants, may lie in the inability of S186A to activate expression of Rta protein. 2008 Virology Result EBV S186A;R179A;Y180E;S186A 62;90;100;143 67;95;105;148 BRLF1 175 178 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. PAA and ACV treatment did not alter the formation of discrete punctate ZEBRA foci by the R179A ZEBRA mutant. 2008 Virology Result EBV R179A 89 94 BZLF1;BZLF1 71;95 76;100 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. Previous experiments have shown that exogenous expression of Rta rescues BMRF1 transcriptional activation by the S186A ZEBRA mutant. 2008 Virology Result EBV S186A 113 118 BMRF1;BZLF1;BRLF1 73;119;61 78;124;64 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. S186A is a well-studied ZEBRA mutant which is defective at disruption of latency due to an inability to activate expression of Rta. 2008 Virology Result EBV S186A 0 5 BZLF1;BRLF1 24;127 29;130 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. S186E was smoothly and diffusely distributed throughout the intranuclear space; no discrete puncta were seen in any cell; and as was seen with S186A, sub-regions of reduced S186E staining were present. 2008 Virology Result EBV S186E;S186A;S186E 0;143;173 5;148;178 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. Since the Y180E mutant is defective at lytic viral DNA replication, these findings provide further evidence that globules containing EA-D are sites of accumulation of lytically replicated EBV DNA. 2008 Virology Result EBV Y180E 10 15 BMRF1 133 137 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. Some of the EA-D-positive D98/HR-1 cells observed after transfection of R179A displayed a wild-type phenotype: EA-D was localized to globular replication compartments. 2008 Virology Result EBV R179A 72 77 BMRF1;BMRF1 12;111 16;115 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. Sub-regions of reduced or no mutant S186A ZEBRA staining were also observed. 2008 Virology Result EBV S186A 36 41 BZLF1 42 47 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. Sub-regions with little or no ZEBRA staining, consistent with nucleoli and similar to those observed with WT and S186A, were often seen. 2008 Virology Result EBV S186A 113 118 BZLF1 30 35 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. The differences in distribution of R179A or Y180E mutant ZEBRA proteins in 293 cell backgrounds with and without an EBV genome suggests two possibilities which are not mutually exclusive: (1) the mutation in the basic domain itself may affect intra-nuclear localization of ZEBRA protein, even in EBV-negative cells; or (2) cellular and viral factors may partially contribute to the mutant speckled phenotype seen in cells containing EBV bacmids. 2008 Virology Result EBV R179A;Y180E 35;44 40;49 BZLF1;BZLF1 57;273 62;278 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. The diffuse distribution of ZEBRA S186A mutant in 2089 cells differs from the punctate distribution of ZEBRA induced by the R179A and Y180E mutants. 2008 Virology Result EBV S186A;R179A;Y180E 34;124;134 39;129;139 BZLF1;BZLF1 28;103 33;108 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. The distribution of R179A and Y180E mutant ZEBRA proteins in 293 cells differed from the smooth diffuse distribution of wild-type ZEBRA and S186A in the same cells, and also differed from the discretely speckled localization of these two mutants in cells containing EBV-bacmids. 2008 Virology Result EBV R179A;Y180E;S186A 20;30;140 25;35;145 BZLF1;BZLF1 43;130 48;135 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. The distribution of Rta in 2089 cells transfected with K188R ZEBRA mutant was the same as the distribution of Rta in cells transfected with wild-type ZEBRA. 2008 Virology Result EBV K188R 55 60 BZLF1;BZLF1;BRLF1;BRLF1 61;150;20;110 66;155;23;113 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. The distribution of S186E ZEBRA appeared similar to S186A. 2008 Virology Result EBV S186E;S186A 20;52 25;57 BZLF1 26 31 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. The few cells transfected with Y180E which showed Rta in globules were also the only ones to show EA-D in globular compartments. 2008 Virology Result EBV Y180E 31 36 BMRF1;BRLF1 98;50 102;53 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. The inability of either R179A or Y180E mutant to produce in 293 cells the numerous clearly distinct evenly distributed punctate foci which were seen in 2089 or BZKO cells suggests that additional viral factors conferred by lytic EBV infection are likely to be necessary to produce the speckled phenotype (see Discussion). 2008 Virology Result EBV R179A;Y180E 24;33 29;38 EBV infections 229 242 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. The intra-nuclear distribution of S186A mutant ZEBRA in BZKO and 2089 cells was similar to wild-type ZEBRA. 2008 Virology Result EBV S186A 34 39 BZLF1;BZLF1 47;101 52;106 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. The localization of EA-D following lytic cycle activation by Y180E differed from that induced by wild-type ZEBRA protein. 2008 Virology Result EBV Y180E 61 66 BZLF1;BMRF1 107;20 112;24 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. The localization of S186A mutant ZEBRA therefore differed from other Rta-deficient ZEBRA mutants. 2008 Virology Result EBV S186A 20 25 BZLF1;BZLF1;BRLF1 33;83;69 38;88;72 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. The mutants which were studied in this experiment were: 1) S186A, defective at induction of Rta expression; 2) R179A, active at inducing Rta, but defective at inducing EA-D; 3) Y180E, active at inducing EA-D, but defective at activating lytic viral DNA synthesis and late protein expression; and 4) K188R, a mutant indistinguishable from wild-type (Table 1). 2008 Virology Result EBV S186A;R179A;Y180E;K188R 59;111;177;299 64;116;182;304 BMRF1;BMRF1;BRLF1;BRLF1 168;203;92;137 172;207;95;140 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. The next experiments attempted to determine whether the speckled distribution of ZEBRA, observed with a mutant, such as R179A, that does not induce viral replication, could be reproduced with wild-type ZEBRA when lytic viral DNA replication was inhibited by anti-viral drugs. 2008 Virology Result EBV R179A 120 125 BZLF1;BZLF1 81;202 86;207 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. The non-uniform and uneven distribution of R179A and Y180E proteins observed in 293 cells could be clearly distinguished from the pattern of distinctly-defined and evenly spaced discrete punctate foci seen in 2089 and BZKO cells containing EBV-bacmids. 2008 Virology Result EBV R179A;Y180E 43;53 48;58 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. The speckled distribution of ZEBRA mutants, such as R179A and Y180E, in 293 cells containing EBV-bacmids is a new phenomenon. 2008 Virology Result EBV R179A;Y180E 52;62 57;67 BZLF1 29 34 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. The speckled phenotype of R179A mutant ZEBRA in PAA/ACV-treated cells. 2008 Virology Result EBV R179A 26 31 BZLF1 39 44 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. The transfected S186A ZEBRA protein was confined to the nucleus in a finely-grained, relatively smooth, diffuse pattern. 2008 Virology Result EBV S186A 16 21 BZLF1 22 27 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. The WT-mutant, K188R, activates Rta expression, early gene expression, and late gene expression at levels similar to wild type ZEBRA (; Fig 4). 2008 Virology Result EBV K188R 15 20 BZLF1;BRLF1 127;32 132;35 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. The Y180E mutation therefore allows Rta expression; however, Rta is not found in globular replication compartments, as the result of Y180E's failure to stimulate lytic DNA replication. 2008 Virology Result EBV Y180E;Y180E 133;4 138;9 BRLF1;BRLF1 36;61 39;64 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. Therefore we further tested whether the diffuse distribution of the S186A ZEBRA mutant was altered when Rta was exogenously co-expressed with S186A mutant ZEBRA. 2008 Virology Result EBV S186A;S186A 68;142 73;147 BZLF1;BZLF1;BRLF1 74;155;104 79;160;107 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. Therefore, S186A does not lead to formation of replication compartments. 2008 Virology Result EBV S186A 11 16 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. These foci of EA-D clumps produced in the presence of PAA and ACV were uneven in size, intensity, and spacing and did not resemble the uniformly sized and evenly spaced punctate ZEBRA foci seen with some ZEBRA mutants, such as R179A and Y180E. 2008 Virology Result EBV R179A;Y180E 227;237 232;242 BZLF1;BZLF1;BMRF1 178;204;14 183;209;18 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. These results make it unlikely that the diffuse distribution of S186A is directly related to its capacity to bind DNA. 2008 Virology Result EBV S186A 64 69 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. These results show that viral DNA replication is not required for formation of the speckled ZEBRA foci by the R179A mutant. 2008 Virology Result EBV R179A 110 115 BZLF1 92 97 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. These results showed that the diffuse distribution of Z(S186A) is an intrinsic property of the mutant protein and is not correlated with its failure to activate Rta or EA-D expression. 2008 Virology Result EBV S186A 56 61 BMRF1;BRLF1;BZLF1 168;161;54 172;164;55 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. Thus, like wild-type ZEBRA, K188R was also partially recruited to viral replication compartments. 2008 Virology Result EBV K188R 28 33 BZLF1 21 26 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. Thus, the intra-nuclear distribution of wild-type, S186A, and K188R mutant ZEBRA proteins was indistinguishable in EBV-positive and EBV-negative 293 cells. 2008 Virology Result EBV S186A;K188R 51;62 56;67 BZLF1 75 80 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. To determine the effects of the Y180E and K188R ZEBRA mutants on Rta distribution, 2089 cells transfected with Y180E ZEBRA or K188R ZEBRA were observed for Rta expression at 42 hours post-transfection. 2008 Virology Result EBV Y180E;K188R;Y180E;K188R 32;42;111;126 37;47;116;131 BZLF1;BZLF1;BZLF1;BRLF1;BRLF1 48;117;132;65;156 53;122;137;68;159 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. To determine whether WT or R179A mutant ZEBRA would form discrete speckled punctate foci in other cell lines infected with EBV, we examined ZEBRA and EA-D localization in D98/HR-1 cells transfected with WT ZEBRA or R179A mutant ZEBRA. 2008 Virology Result EBV R179A;R179A 27;215 32;220 BZLF1;BZLF1;BZLF1;BZLF1;BMRF1 40;140;206;228;150 45;145;211;233;154 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. To observe the effect of inhibiting viral DNA synthesis on the localization of ZEBRA and EA-D proteins, both of which are presumptive components of an EBV pre-replication complex, 2089 cells were transfected with WT or R179A mutant ZEBRA and treated with PAA or ACV. 2008 Virology Result EBV R179A 219 224 BZLF1;BZLF1;BMRF1 79;232;89 84;237;93 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. To observe the intracellular distribution of the ZEBRA mutants in cells lacking an EBV genome, and more specifically to test whether the formation of punctate ZEBRA foci observed with the R179A and Y180E mutations required additional viral factors, each ZEBRA mutant was transfected into 293 cells devoid of an EBV-bacmid. 2008 Virology Result EBV R179A;Y180E 188;198 193;203 BZLF1;BZLF1;BZLF1 49;159;254 54;164;259 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. To test whether the diffuse distribution of the S186A mutant ZEBRA was common to other ZEBRA mutants deficient at activation of Rta and EA-D, we studied the distribution of two additional mutants, K181A and A185V. 2008 Virology Result EBV S186A;K181A;A185V 48;197;207 53;202;212 BZLF1;BZLF1;BMRF1;BRLF1 61;87;136;128 66;92;140;131 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. Transfection of K181A. 2008 Virology Result EBV K181A 16 21 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. Transfection of K188R mutant into 293 cells, similarly to wild-type ZEBRA, produced a diffuse fine-grain intranuclear distribution. 2008 Virology Result EBV K188R 16 21 BZLF1 68 73 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. Transfection of S186A mutant into 293 cells also produced a diffuse and smoothly textured intra-nuclear distribution. 2008 Virology Result EBV S186A 16 21 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. Transfection with Y180E ZEBRA caused Rta to be localized either diffusely and uniformly. 2008 Virology Result EBV Y180E 18 23 BZLF1;BRLF1 24;37 29;40 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. We also compared the distribution of the S186A mutant with the distribution of another mutant at the same position, S186E. 2008 Virology Result EBV S186A;S186E 41;116 46;121 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. When transfected into BZKO and 2089 cells the late ZEBRA mutant Y180E also localized to numerous discrete punctate foci. 2008 Virology Result EBV Y180E 64 69 BZLF1 51 56 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. Yet regardless of the level of wild-type ZEBRA protein expressed in any given cell, the discrete foci seen with R179A was not seen in cells transfected with wild-type ZEBRA. 2008 Virology Result EBV R179A 112 117 BZLF1;BZLF1 41;167 46;172 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. ZEBRA staining in K188R-transfected cells was diffuse throughout the nucleus with a relatively smooth texture. 2008 Virology Result EBV K188R 18 23 BZLF1 0 5 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. 2) behaved like wild-type in activating EA-D, alone and in synergy with Z(S186A), and in activation of BLRF2. 2009 Virology Result EBV S186A 74 79 BLRF2;BMRF1;BZLF1 103;40;72 108;44;73 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. 2B, lane 5); however, the mutant H589A/H592A did not bind to BMLF1 RRE (lane 6). 2009 Virology Result EBV H589A;H592A 33;39 38;44 BMLF1 61 66 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. 5 through 7 demonstrated that the Rta (F600A/F605A) mutant was a relatively deficient activator of EBV lytic genes, we explored the possibility that Rta (F600A/F605A) mutations impinge on the transcriptional activation function of Rta when fused to a heterologous DNA binding domain. 2009 Virology Result EBV F600A;F605A;F600A;F605A 39;45;154;160 44;50;159;165 BRLF1;BRLF1;BRLF1 34;149;231 37;152;234 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. 5A (lane 3) and 5B (lane 3) show that two deletion mutants of Rta which were enhanced in DNA binding did not detectably activate EA-D protein when they were introduced into BZKO cells together with Z(S186A). 2009 Virology Result EBV S186A 200 205 BMRF1;BRLF1;BZLF1 129;62;198 133;65;199 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. 6) compared transcriptional activation by the Rta (F600A/F605A) (FA) mutant with wild-type Rta in a broader range of biologic assays than synergy with Z (S186A). 2009 Virology Result EBV F600A;F605A;S186A 51;57;154 56;62;159 BRLF1;BRLF1;BZLF1 46;91;151 49;94;152 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. 6E, lane 3); it could synergize with Z(S186A), but the signal of EA-D in the presence of Z(S186A) was also slightly reduced by comparison to wild-type. 2009 Virology Result EBV S186A;S186A 39;91 44;96 BMRF1;BZLF1;BZLF1 65;37;89 69;38;90 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. 6E; lanes 2-4); the addition of the ZEBRA mutant Z(S186A), which by itself manifests no activity (lane 5), leads to strong synergistic activation of EA-D by Rta and ZEBRA. 2009 Virology Result EBV S186A 51 56 BZLF1;BZLF1;BMRF1;BRLF1;BZLF1 36;165;149;157;49 41;170;153;160;50 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. As observed in vitro, Rta (F600A/ F605A) showed stronger DNA binding in vivo on the BHLF1 promoter than wild-type Rta. 2009 Virology Result EBV F600A;F605A 27;34 32;39 BHLF1;BRLF1;BRLF1 84;22;114 89;25;117 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. F600A/F605A mutations weaken the transactivation domain of Rta fused to the DNA binding domain of GAL4. 2009 Virology Result EBV F600A;F605A 0;6 5;11 BRLF1 59 62 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. GAL4-Rta chimeras containing the GAL4 DNA binding domain (aa 1-147) fused to the Rta transactivation domain (aa 416-605), and similar chimeras containing the Rta (F600A/F605A) mutations, were examined in parallel for their capacity to activate a reporter consisting of five GAL4 binding sites upstream of the adenovirus E1B minimal promoter fused to CAT. 2009 Virology Result EBV F600A;F605A 163;169 168;174 BRLF1;BRLF1;BRLF1 5;81;158 8;84;161 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. HKB5/Cl8 cells were transfected with plasmids expressing wild-type FLAG-Rta, FLAG-Rta (F600A/F605A) and FLAG-Rta (R162A), a mutant of Rta that was deficient in binding to DNA by EMSA (data not shown). 2009 Virology Result EBV F600A;F605A;R162A 87;93;114 92;98;119 BRLF1;BRLF1;BRLF1;BRLF1 72;82;109;134 75;85;112;137 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. However, the S598A mutant protein behaved like wild-type Rta; the interaction between S598A and a duplex oligonucleotide containing the RRE from the BMLF1 promoter was very weak. 2009 Virology Result EBV S598A;S598A 13;86 18;91 BMLF1;BRLF1 149;57 154;60 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. In an initial attempt to characterize the biologic phenotype of Rta mutants with enhanced DNA binding activity two deletion mutants, R (1-595) and R (1-550), and the F600A/F605A double point mutant were evaluated for their capacity to activate expression of EA-D (early antigen-diffuse), the product of the EBV BMRF1 gene, encoding the DNA polymerase processivity factor. 2009 Virology Result EBV F600A;F605A 166;172 171;177 BMRF1;BMRF1;BRLF1 311;258;64 316;262;67 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. In Raji cells the Rta (F600A/F605A) mutant was slightly reduced in its ability to activate EA-D. 2009 Virology Result EBV F600A;F605A 23;29 28;34 BMRF1;BRLF1 91;18 95;21 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. Installing the F600A/F605A mutation in Rta (aa 555-605) restored DNA binding by the F350+ (550-605) Rta deletion mutant protein. 2009 Virology Result EBV F600A;F605A 15;21 20;26 BRLF1;BRLF1 39;100 42;103 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. Rta (F600A/F605A) is a weaker transactivator than wild-type Rta. 2009 Virology Result EBV F600A;F605A 5;11 10;16 BRLF1;BRLF1 0;60 3;63 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. Rta (F600A/F605A) is enhanced in binding DNA in vitro. 2009 Virology Result EBV F600A;F605A 5;11 10;16 BRLF1 0 3 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. Since EMSA demonstrated enhanced DNA binding activity by Rta (F600A/F605A) in vitro, we carried out chromatin immunoprecipitation (ChIP) experiments to determine whether enhanced DNA binding activity of this mutant was also detected in EBV-infected cells. 2009 Virology Result EBV F600A;F605A 62;68 67;73 BRLF1 57 60 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. Since transcriptional activation of the GAL4-Rta fusion proteins was mediated through the DNA binding domain of GAL4 and the transactivation domain of Rta, these experiments suggested that the F600A/F605A mutations directly decreased the transcription activation function of Rta. 2009 Virology Result EBV F600A;F605A 193;199 198;204 BRLF1;BRLF1;BRLF1 45;151;275 48;154;278 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. The activity of the GAL4-Rta (F600A/F605A) mutant was similar to that of GAL4-VP16; it retained only 30% of the activity of GAL4-Rta. 2009 Virology Result EBV F600A;F605A 30;36 35;41 BRLF1;BRLF1 25;129 28;132 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. The deleterious effects of the FA point mutants on synergy of Rta with Z(S186A) were not as pronounced in Raji cells as in BZKO cells (compare. 2009 Virology Result EBV S186A 73 78 BRLF1;BZLF1 62;71 65;72 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. The double point mutant F600A/F605A manifested stronger DNA binding activity than either single point mutant, F600A or F605A. 2009 Virology Result EBV F600A;F605A;F600A;F605A 24;30;110;119 29;35;115;124 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. The effect of the F600A/F605A mutations on the capacity of Rta to activate its target genes and to synergize with Z(S186A) was also examined by immunoblotting in Raji cells. 2009 Virology Result EBV F600A;F605A;S186A 18;24;116 23;29;121 BRLF1;BZLF1 59;114 62;115 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. The expression level of S598A mutant was similar to full-length Rta. 2009 Virology Result EBV S598A 24 29 BRLF1 64 67 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. The F600A/F605A mutant had weak activity in the assay of synergy with Z(S186A), approximately 19% of the activity of wild-type Rta protein. 2009 Virology Result EBV F600A;F605A;S186A 4;10;72 9;15;77 BRLF1;BZLF1 127;70 130;71 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. The F600A/F605A mutation enhances binding of Rta to DNA in vivo. 2009 Virology Result EBV F600A;F605A 4;10 9;15 BRLF1 45 48 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. The level of internal control GAPDH (glyceraldehyde-3-phosphate dehydrogenase) mRNA was the same in cells transfected with wild-type or F600A/F605A. 2009 Virology Result EBV F600A;F605A 136;142 141;147 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. The mutant F600A/F605A was markedly enhanced in DNA binding. 2009 Virology Result EBV F600A;F605A 11;17 16;22 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. The mutant Rta (F600A/F605A) protein was more abundantly expressed than wild-type Rta or the mutant of Rta (H589A/H592A). 2009 Virology Result EBV F600A;F605A;H589A;H592A 16;22;108;114 21;27;113;119 BRLF1;BRLF1;BRLF1 11;82;103 14;85;106 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. The mutant Rta (H589A/H592A). 2009 Virology Result EBV H589A;H592A 16;22 21;27 BRLF1 11 14 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. The R162A mutant did not detectably bind the BHLF1 promoter in this ChIP assay. 2009 Virology Result EBV R162A 4 9 BHLF1 45 50 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. The restoration of DNA binding ability in the mutants F600A/F605A, F600A and F605A was unrelated to their protein expression level; all Rta mutants were expressed similarly in cell extracts used for EMSA. 2009 Virology Result EBV F600A;F605A;F600A;F605A 54;60;67;77 59;65;72;82 BRLF1 136 139 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. The Rta (F600A/F605A) mutant was also markedly defective in activating BLRF2 in BZKO cells (data not shown). 2009 Virology Result EBV F600A;F605A 9;15 14;20 BLRF2;BRLF1 71;4 76;7 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. The Rta (F600A/F605A) mutant was markedly impaired at activating BLRF2, both in the absence and presence of Z(S186A) (lane 3 and lane 7). 2009 Virology Result EBV F600A;F605A;S186A 9;15;110 14;20;115 BLRF2;BRLF1;BZLF1 65;4;108 70;7;109 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. The two mutants with aromatic substitutions, F600W/F605W and F600Y/F605Y, both bound DNA weakly. 2009 Virology Result EBV F600W;F605W;F600Y;F605Y 45;51;61;67 50;56;66;72 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. The ZEBRA mutant Z(S186A) does not by itself activate BMRF1, but can synergize with Rta to activate expression of this gene, both the transcript and the protein. 2009 Virology Result EBV S186A 19 24 BMRF1;BZLF1;BRLF1;BZLF1 54;4;84;17 59;9;87;18 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. Thus, whether assessed by reporter assays or assays for EBV lytic gene expression, at the level of viral transcripts or viral polypeptide expression, Rta (F600A/F605A), which manifests stronger DNA binding activity than wild-type Rta, was consistently defective as a transactivator. 2009 Virology Result EBV F600A;F605A 155;161 160;166 BRLF1;BRLF1 150;230 153;233 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. Two single point mutants, F600A and F605A, each enhanced DNA binding by Rta. 2009 Virology Result EBV F600A;F605A 26;36 31;41 BRLF1 72 75 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. Unlike the synergistic activation of the BMRF1 promoter, the activation of BLRF2 was not enhanced by co-transfection of the Z(S186A) mutant. 2009 Virology Result EBV S186A 126 131 BLRF2;BMRF1;BZLF1 75;41;124 80;46;125 19325883 Methylation-dependent binding of the epstein-barr virus BZLF1 protein to viral promoters. As previously reported, the Z(S186A) mutant by itself was not able to induce expression of the R protein, or the early viral protein EA-D (BMRF1). 2009 PLoS pathogens Result EBV S186A 30 35 BMRF1;BMRF1;BZLF1 139;133;28 144;137;29 19325883 Methylation-dependent binding of the epstein-barr virus BZLF1 protein to viral promoters. As previously reported, Z(S186A) was also defective in activating the methylated form of Rp. 2009 PLoS pathogens Result EBV S186A 26 31 BZLF1 24 25 19325883 Methylation-dependent binding of the epstein-barr virus BZLF1 protein to viral promoters. Consistent with its inability to bind to methylated Nap ZRE1 and ZRE2 in the EMSAs, Z(S186A) was impaired in the ability to activate the methylated form of Nap. 2009 PLoS pathogens Result EBV S186A 86 91 BZLF1 84 85 19325883 Methylation-dependent binding of the epstein-barr virus BZLF1 protein to viral promoters. Furthermore, in comparison to wild-type Z, the Z(S186A) mutant was also impaired for the ability to activate expression of Na, and this defect persisted even when the R protein was supplied in trans. 2009 PLoS pathogens Result EBV S186A 49 54 BZLF1;BZLF1 40;47 41;48 19325883 Methylation-dependent binding of the epstein-barr virus BZLF1 protein to viral promoters. However, in combination with an R expression vector, Z(S186A) activated EA-D, consistent with the known ability of this mutant to bind to the BMRF1 promoter ZREs. 2009 PLoS pathogens Result EBV S186A 55 60 BMRF1;BMRF1;BZLF1 142;72;53 147;76;54 19325883 Methylation-dependent binding of the epstein-barr virus BZLF1 protein to viral promoters. In addition, this architecture explains why mutation of Ser186 to alanine, which would attenuate this hydrogen bonding network, greatly abrogates Z binding to methylated Nap ZRE2. 2009 PLoS pathogens Result EBV S186A 56 73 BZLF1 146 147 19325883 Methylation-dependent binding of the epstein-barr virus BZLF1 protein to viral promoters. More recently, converting Z residue Cys189 to a serine residue was reported to inhibit Z binding to methylated Rp ZRE3, but not AP1. 2009 PLoS pathogens Result EBV C189S 36 54 BZLF1;BZLF1 26;87 27;88 19325883 Methylation-dependent binding of the epstein-barr virus BZLF1 protein to viral promoters. Mutation of Cys189 to a serine residue. 2009 PLoS pathogens Result EBV C189S 12 30 19325883 Methylation-dependent binding of the epstein-barr virus BZLF1 protein to viral promoters. The methylated forms of the Nap-LUC or Rp-LUC vectors were co-transfected into HeLa cells with a control vector or vectors expressing either wild-type Z or Z(S186A). 2009 PLoS pathogens Result EBV S186A 158 163 BZLF1;BZLF1 151;156 152;157 19325883 Methylation-dependent binding of the epstein-barr virus BZLF1 protein to viral promoters. The Z(C189S) mutant was similar to wild-type Z in its ability to activate R, EA-D and Na expression, consistent with its ability to bind (at least weakly) to one or more ZREs in each promoter. 2009 PLoS pathogens Result EBV C189S 6 11 BMRF1;BZLF1;BZLF1 77;4;45 81;5;46 19325883 Methylation-dependent binding of the epstein-barr virus BZLF1 protein to viral promoters. The Z(C189S) mutant was slightly impaired for binding to the methylated forms of the Rp ZRE2 and Nap ZRE2 sites, but highly impaired for binding to the methylated forms of Nap ZRE1 and Rp ZRE3. 2009 PLoS pathogens Result EBV C189S 6 11 BZLF1 4 5 19325883 Methylation-dependent binding of the epstein-barr virus BZLF1 protein to viral promoters. The Z(S186A) mutant was highly impaired in comparison to wild-type Z for binding to the methylated forms of the Nap ZRE1 and ZRE2 sites, as well as the Rp ZRE2 and ZRE3 sites, but, as expected, was able to bind to the consensus AP1 site at least as well as wild-type Z. 2009 PLoS pathogens Result EBV S186A 6 11 BZLF1;BZLF1;BZLF1 4;67;267 5;68;268 19325883 Methylation-dependent binding of the epstein-barr virus BZLF1 protein to viral promoters. Thus, the previously reported finding that the Z(S186A) mutant is unable to disrupt viral latency in the context of the intact viral genome may reflect not only its inability to activate the Rp, but also its inability to activate the Nap. 2009 PLoS pathogens Result EBV S186A 49 54 BZLF1 47 48 19325883 Methylation-dependent binding of the epstein-barr virus BZLF1 protein to viral promoters. To determine if Z binding to the methylated form of the Nap is required for Z activation of Na expression in the context of the intact viral genome, we compared the ability of wild-type Z, the Z(S186A) mutant, or the Z(C189S) mutant to activate Na expression in the presence or absence of an R expression vector in 293 cells stably infected with a BZLF1-deleted mutant EBV. 2009 PLoS pathogens Result EBV S186A;C189S 195;219 200;224 BZLF1;BZLF1;BZLF1;BZLF1;BZLF1;BZLF1 348;16;76;186;193;217 353;17;77;187;194;218 19325883 Methylation-dependent binding of the epstein-barr virus BZLF1 protein to viral promoters. To determine whether Z residue 186 or 189 regulates Z binding to methylated ZREs in Nap, we compared the ability of in vitro-translated wild-type Z, Z(S186A) and Z(C189S) to bind to labeled oligonucleotide probes containing the Nap ZRE1 and ZRE2 sites, the consensus AP1 site from the BMRF1 early viral promoter, or the Rp ZRE2 and ZRE3 sites. 2009 PLoS pathogens Result EBV S186A;C189S 151;164 156;169 BMRF1;BZLF1;BZLF1;BZLF1;BZLF1;BZLF1 285;21;52;146;149;162 290;22;53;147;150;163 19325883 Methylation-dependent binding of the epstein-barr virus BZLF1 protein to viral promoters. To determine whether Z residue Ser186 is required for activation of the methylated Nap in vivo, we compared the ability of wild-type Z, versus the Z(S186A) mutant, to activate the methylated Nap-LUC construct. 2009 PLoS pathogens Result EBV S186A 149 154 BZLF1;BZLF1;BZLF1 21;133;147 22;134;148 19325883 Methylation-dependent binding of the epstein-barr virus BZLF1 protein to viral promoters. Wild-type Z but not Z(S186A) activates Na and R expression in latently infected 293 cells. 2009 PLoS pathogens Result EBV S186A 22 27 BZLF1;BZLF1 10;20 11;21 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. 10A compare lane 3 to 4 and 13 to 14), addition of the primase alone had no significant effect on the level of the FR3 protein as compared to cells transfected with the S173A mutant in absence of RP. 2010 PLoS pathogens Result EBV S173A 169 174 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. 1A, C and D compare the phenotype of Z(R187K) to wt ZEBRA, Z(K188A) and Z(F193E). 2010 PLoS pathogens Result EBV R187K;K188A;F193E 39;61;74 44;66;79 BZLF1;BZLF1;BZLF1;BZLF1 52;37;59;72 57;38;60;73 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. 3.7-fold less oriLyt was immunoprecipitated from cells expressing Z(Y180E) compared to those expressing wt ZEBRA. 2010 PLoS pathogens Result EBV Y180E 68 73 BZLF1;BZLF1 107;66 112;67 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. 5 compares the DNA binding activity of Z(Y180E) and K(188A) with that of wt ZEBRA and with Z(K188R), a mutant with a conservative change that manifests a wild phenotype. 2010 PLoS pathogens Result EBV Y180E;K188R 41;93 46;98 BZLF1;BZLF1;BZLF1 76;39;91 81;40;92 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. 9A, BZKO cells were transfected with empty vector (CMV), Z(S173A) or wt ZEBRA in the presence and absence of the six EBV replication proteins. 2010 PLoS pathogens Result EBV S173A 59 64 BZLF1;BZLF1 72;57 77;58 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. A 1.8-fold increase in association with oriLyt was detected with wt ZEBRA; 2.2-fold with Z(S173A); 3-fold with Z(Y180E), and 4.24-fold with Z(S167A/S173A). 2010 PLoS pathogens Result EBV S173A;Y180E;S167A;S173A 91;113;142;148 96;118;147;153 BZLF1;BZLF1;BZLF1;BZLF1 68;89;111;140 73;90;112;141 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. A biological replicate experiment was performed and included two additional ZEBRA RD mutants, Z(Y180E) and Z(S167A/S173A). 2010 PLoS pathogens Result EBV Y180E;S167A;S173A 96;109;115 101;114;120 BZLF1;BZLF1;BZLF1 76;94;107 81;95;108 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. A mixture of the primase, the single-stranded DNA binding protein and the DNA polymerase processivity factor suppressed the defect in Z(S173A) and restored replication to approximately 44% that of the level activated by the wild type protein. 2010 PLoS pathogens Result EBV S173A 136 141 BZLF1 134 135 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. A significant 2.4-fold to 3.6-fold increase in the level of the brlf1 transcript was detected when BALF2, BMRF1 and BSLF1 were co-expressed with each of the three DNA binding domain ZEBRA mutants, Z(Y180E), Z(R187K) and Z(K188A). 2010 PLoS pathogens Result EBV Y180E;R187K;K188A 199;209;222 204;214;227 BMRF1;BRLF1;BSLF1;BZLF1;BALF2;BZLF1;BZLF1;BZLF1 106;64;116;182;99;197;207;220 111;69;121;187;104;198;208;221 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. Addition of all replication proteins induced viral replication 2.2-fold above that induced by Z(R187K) alone. 2010 PLoS pathogens Result EBV R187K 96 101 BZLF1 94 95 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. As expected, Z(Y180E) was impaired in activating late gene expression while the revertant mutant Z(Y180E Y) was competent to activate late gene expression to the same level as wt ZEBRA. 2010 PLoS pathogens Result EBV Y180E;Y180E 15;99 20;104 BZLF1;BZLF1;BZLF1 179;13;97 184;14;98 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. Based on these results and our previous studies, we conclude that RD mutants Z(S173A), Z(Y180E), Z(R187K), and Z(K188A) are competent to activate expression of early viral proteins but incompetent to activate lytic viral DNA replication and late gene expression (see also. 2010 PLoS pathogens Result EBV S173A;Y180E;R187K;K188A 79;89;99;113 84;94;104;118 BZLF1;BZLF1;BZLF1;BZLF1 77;87;97;111 78;88;98;112 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. Both Z(Y180E) and Z(K188A) were markedly impaired in binding to each of the four probes relative to wt ZEBRA. 2010 PLoS pathogens Result EBV Y180E;K188A 7;20 12;25 BZLF1;BZLF1;BZLF1 103;5;18 108;6;19 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. BZKO cells were transfected with expression vectors encoding Z(S167A/S173A), Z(S173A), Z(Y180E), Z(R187K), Z(K188A) and wild type ZEBRA in the absence and presence of plasmids encoding the tripartite mixture of replication proteins. 2010 PLoS pathogens Result EBV S167A;S173A;S173A;Y180E;R187K;K188A 63;69;79;89;99;109 68;74;84;94;104;114 BZLF1;BZLF1;BZLF1;BZLF1;BZLF1;BZLF1 130;61;77;87;97;107 135;62;78;88;98;108 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. Expression of high levels of replication proteins reproducibly augmented the capacity of wt ZEBRA and Z(S173A) to stimulate EBV lytic replication by 1.9- and 3.4-fold respectively. 2010 PLoS pathogens Result EBV S173A 104 109 BZLF1;BZLF1 92;102 97;103 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. Expression of Z(R187K) in BZKO cells induced a pattern of lytic gene expression that mimicked Z(K188A); it fully activated expression of two early proteins, Rta and EA-D (aka BMRF1), encoded by brlf1 and bmrf1, but failed to activate synthesis of two late proteins BFRF3 (FR3) (a component of the viral capsid) and BLRF2 (LR2) (a tegument protein). 2010 PLoS pathogens Result EBV R187K;K188A 16;96 21;101 BFRF3;BLRF2;BMRF1;BMRF1;BRLF1;BMRF1;BRLF1;BZLF1;BZLF1 265;315;175;204;194;165;157;14;94 270;320;180;209;199;169;160;15;95 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. For example, in case of Z(S173A), expression of replication proteins reproducibly increased FR3 expression by 3.2-fold reaching 55% that of wt ZEBRA alone. 2010 PLoS pathogens Result EBV S173A 26 31 BZLF1;BZLF1 143;24 148;25 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. For example, Z(K188A) activated between 2.3 to 2.6-fold more bblf4 mRNA than wt ZEBRA. 2010 PLoS pathogens Result EBV K188A 15 20 BBLF4;BZLF1;BZLF1 61;80;13 66;85;14 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. For wild type ZEBRA and three of the mutants, Z(S173A), Z(Y180E) and Z(S167A/S173A), we demonstrated an increase in their association with oriLyt as a result of overexpressing the EBV replication proteins. 2010 PLoS pathogens Result EBV S173A;Y180E;S167A;S173A 48;58;71;77 53;63;76;82 BZLF1;BZLF1;BZLF1;BZLF1 14;46;56;69 19;47;57;70 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. However, addition of the single-stranded DNA binding protein to this mixture resulted in the highest impact on viral genome amplification, a 4.2-fold increase compared to replication induced by Z(R187K) alone. 2010 PLoS pathogens Result EBV R187K 196 201 BZLF1 194 195 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. However, these RD mutants displayed higher efficiency to interact with oriLyt and Rp than the non-DNA binding ZEBRA mutant Z(R183E). 2010 PLoS pathogens Result EBV R183E 125 130 BZLF1;BZLF1 110;123 115;124 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. In an iBDA assay, we transfected BZKO cells with a biotinylated upstream region of oriLyt (BUR) together with expression vectors for wt ZEBRA or Z(S173A) in the absence and presence of the tripartite replication mixture. 2010 PLoS pathogens Result EBV S173A 147 152 BZLF1;BZLF1 136;145 141;146 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. In ChIP experiments, we found that BZKO cells transfected with Z(S173A) or wt ZEBRA yielded more oriLyt when replication proteins were co-expressed, 1.58-fold and 1.72-fold, respectively. 2010 PLoS pathogens Result EBV S173A 65 70 BZLF1;BZLF1 78;63 83;64 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. In contrast, omitting the expression vector of BALF5 augmented the capacity of the other five replication proteins to restore viral replication by Z(S173A). 2010 PLoS pathogens Result EBV S173A 149 154 BALF5;BZLF1 47;147 52;148 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. In further exploration of this phenomenon we identified a fourth ZEBRA RD mutant with a conservative arginine to lysine substitution at position 187. 2010 PLoS pathogens Result EBV R187K 101 148 BZLF1 65 70 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. No difference was detected by ChIP for the effect of replication proteins on the relative binding capacity of Z(R187K) and Z(K188A) to Rp. 2010 PLoS pathogens Result EBV R187K;K188A 112;125 117;130 BZLF1;BZLF1 110;123 111;124 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. Omission of BALF2 and BBLF4 reduced the efficacy of the replication proteins complex to rescue replication by Z(S173A). 2010 PLoS pathogens Result EBV S173A 112 117 BBLF4;BALF2;BZLF1 22;12;110 27;17;111 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. Over-expression of the six EBV replication proteins increased the relative amount of Rp, Zp and BMRF1p DNA precipitated by wt ZEBRA, Z(S167A/S173A) and Z(S173A). 2010 PLoS pathogens Result EBV S167A;S173A;S173A 135;141;154 140;146;159 BZLF1;BZLF1 promoter;BZLF1;BZLF1 126;89;133;152 131;91;134;153 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. Replication proteins had a modest effect on the capacity of wt ZEBRA, Z(S173A) and Z(S167A/S173A) to activate transcription of brlf1 (1.3 to 1.5- fold). 2010 PLoS pathogens Result EBV S173A;S173A;S167A 72;91;85 77;96;90 BRLF1;BZLF1;BZLF1;BZLF1 127;63;70;83 132;68;71;84 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. S2B show that over-expression of replication proteins enhanced the capacity of wt ZEBRA, the phosphorylation site mutants and Z(Y180E) to interact with Rp, the BRLF1 promoter. 2010 PLoS pathogens Result EBV Y180E 128 133 BRLF1;BZLF1;BZLF1 160;82;126 165;87;127 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. Similarly, using quantitative PCR to determine the extent of viral genome amplification, we found the same levels of viral genome in cells expressing Z(S173A) or Z(Y180E) in the absence or presence of BBLF2/3. 2010 PLoS pathogens Result EBV S173A;Y180E 152;164 157;169 BZLF1;BZLF1 150;162 151;163 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. Similarly, Z(R187K) and Z(K188A) pulled down 2.9 and 8.3-fold less DNA than wt ZEBRA. 2010 PLoS pathogens Result EBV R187K;K188A 13;26 18;31 BZLF1;BZLF1;BZLF1 79;11;24 84;12;25 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. The amount of Z(Y180E) bound to Zp and BMRF1p was minimally enhanced by replication factors, 1.3-fold and 1.25-fold, respectively. 2010 PLoS pathogens Result EBV Y180E 16 21 BZLF1 promoter;BZLF1 32;14 34;15 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. The effect of replication proteins on association of ZEBRA with oriLyt was greatest with the mutant Z(S167A/S173A), 6.87-fold. 2010 PLoS pathogens Result EBV S167A;S173A 102;108 107;113 BZLF1;BZLF1 53;100 58;101 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. The effect of replication proteins on the amount of viral DNA pulled down by Z(Y180E) was more pronounced on Rp (2.2-fold). 2010 PLoS pathogens Result EBV Y180E 79 84 BZLF1 77 78 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. The enhancement was most marked for RD mutants Z(Y180E) and Z(R187K). 2010 PLoS pathogens Result EBV Y180E;R187K 49;62 54;67 BZLF1;BZLF1 47;60 48;61 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. The other two mutants, Z(F193E) and Z(K194A), are slightly to moderately impaired in activating viral replication and late gene expression. 2010 PLoS pathogens Result EBV F193E;K194A 25;38 30;43 BZLF1;BZLF1 23;36 24;37 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. The same impairment of binding was detected between Z(S173A) and the Rta promoter, but Z(S173A) was competent to activate expression of Rta to the same extent as wt ZEBRA. 2010 PLoS pathogens Result EBV S173A;S173A 54;89 59;94 BZLF1;BRLF1;BRLF1;BZLF1;BZLF1 165;69;136;52;87 170;72;139;53;88 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. The two late mutants Z(R187K) and Z(K188A) failed to induce the replication ladder. 2010 PLoS pathogens Result EBV R187K;K188A 23;36 28;41 BZLF1;BZLF1 21;34 22;35 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. The two ZEBRA RD mutants which were most defective in binding to oriLyt, namely Z(R187K) and Z(K188A) were the least affected by replication proteins. 2010 PLoS pathogens Result EBV R187K;K188A 82;95 87;100 BZLF1;BZLF1;BZLF1 8;80;93 13;81;94 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. The Z(R183E) mutant pulled down amounts of oriLyt and Rp that were equivalent to those detected in ChIP experiments performed with cells transfected with empty vector or precipitated with pre-immune serum. 2010 PLoS pathogens Result EBV R183E 6 11 BZLF1 4 5 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. The ZEBRA mutant, Z(K188R), which is fully competent to activate the lytic cycle, shifted the same set of ZEBRA specific DNA probes to percentages that were markedly higher than those observed with the ZEBRA RD mutants, namely 12.3% and 38.8% of the total probe. 2010 PLoS pathogens Result EBV K188R 20 25 BZLF1;BZLF1;BZLF1;BZLF1 4;106;202;18 9;111;207;19 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. The ZEBRA mutants that reproducibly exhibited replication defective phenotype were: Z(S173A) in the regulatory domain and Z(Y180E) and Z(K188A) in the DNA recognition domain. 2010 PLoS pathogens Result EBV S173A;Y180E;K188A 86;124;137 91;129;142 BZLF1;BZLF1;BZLF1;BZLF1 4;84;122;135 9;85;123;136 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. The ZEBRA RD mutants, Z(S173A), Z(Y180E), Z(R187K) and Z(K188A), reproducibly activated expression of the brlf1 message to levels similar or higher than that of wt ZEBRA. 2010 PLoS pathogens Result EBV S173A;Y180E;R187K;K188A 24;34;44;57 29;39;49;62 BRLF1;BZLF1;BZLF1;BZLF1;BZLF1;BZLF1;BZLF1 106;4;164;22;32;42;55 111;9;169;23;33;43;56 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. These in vitro DNA binding studies clearly indicated that Z(Y180E) and Z(K188A) are both significantly impaired in their capacity to bind to ZEBRA response elements present in regulatory sites for transcription or replication. 2010 PLoS pathogens Result EBV Y180E;K188A 60;73 65;78 BZLF1;BZLF1;BZLF1 141;58;71 146;59;72 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. These results suggest that amino acid changes introduced in the three ZEBRA RD mutants did not completely abolish interaction of ZEBRA with oriLyt as was observed with the non DNA binding mutation R183E. 2010 PLoS pathogens Result EBV R183E 197 202 BZLF1;BZLF1 70;129 75;134 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. Three of these mutants, Z(Y180E), Z(K188A) and Z(R187K), are markedly defective in activating late gene expression and viral replication. 2010 PLoS pathogens Result EBV Y180E;K188A;R187K 26;36;49 31;41;54 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. To delineate the contribution of each replication protein in restoring lytic viral DNA synthesis, Z(S173A) was co-expressed with different mixtures of replication proteins. 2010 PLoS pathogens Result EBV S173A 100 105 BZLF1 98 99 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. To demonstrate that the introduced point mutations were the sole cause for the observed defect in late gene expression, the mutant Z(Y180E) was reverted to its original amino acid composition. 2010 PLoS pathogens Result EBV Y180E 133 138 BZLF1 131 132 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. To determine if the same tripartite mixture of replication proteins could complement the defect in viral genome amplification observed in ZEBRA mutants in the DNA recognition domain, we repeated the same experiment using Z(R187K). 2010 PLoS pathogens Result EBV R187K 223 228 BZLF1;BZLF1 138;221 143;222 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. To determine whether ectopic expression of BBLF2/3 could rescue the defect in these mutants, we co-expressed BBLF2/3 with two ZEBRA RD mutants, Z(S173A) and Z(Y180E), in BZKO cells. 2010 PLoS pathogens Result EBV S173A;Y180E 146;159 151;164 BZLF1;BZLF1;BZLF1 126;144;157 131;145;158 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. To examine whether the defect in late gene expression was due to a failure in stimulating viral replication, we tested the capacity of Z(R187K) to induce viral genome amplification by probing for two different regions of viral DNA. 2010 PLoS pathogens Result EBV R187K 137 142 BZLF1 135 136 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. To study the associations of the three basic domain ZEBRA RD mutants with oriLyt we transfected BZKO cells with expression vectors encoding each of the ZEBRA RD mutants, wt ZEBRA and a non-DNA binding form of ZEBRA, Z(R183E), which does not activate transcription or replication. 2010 PLoS pathogens Result EBV R183E 218 223 BZLF1;BZLF1;BZLF1;BZLF1;BZLF1 52;152;173;209;216 57;157;178;214;217 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. Transfection of the primase and the DNA polymerase processivity factor together with Z(R187K) had no effect on late gene expression or viral DNA synthesis. 2010 PLoS pathogens Result EBV R187K 87 92 BZLF1 85 86 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. Using quantitative RT-PCR we assessed the level of transcripts encoding the heterotrimeric helicase-primase complex in cells expressing five RD mutants: the regulatory mutants, Z(S173A) and Z(S167A/S173A) and the three basic domain mutants, Z(Y180E), Z(R187K) and Z(K188A). 2010 PLoS pathogens Result EBV S173A;S173A;S167A;Y180E;R187K;K188A 179;198;192;243;253;266 184;203;197;248;258;271 BZLF1;BZLF1;BZLF1;BZLF1;BZLF1 177;190;241;251;264 178;191;242;252;265 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. We found that all ZEBRA RD mutants were more efficient than the non-DNA binding mutant Z(R183E), but less competent than wt ZEBRA in precipitating the upstream region of oriLyt. 2010 PLoS pathogens Result EBV R183E 89 94 BZLF1;BZLF1;BZLF1 18;124;87 23;129;88 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. We found that co-expression of the six core components of the replication machinery enhanced binding of wt ZEBRA, Z(Y180E), Z(R187K) and Z(S173A) to oriLyt by 2.1-, 6.0-, 16.4- and 5.0-fold, respectively. 2010 PLoS pathogens Result EBV Y180E;R187K;S173A 116;126;139 121;131;144 BZLF1;BZLF1;BZLF1;BZLF1 107;114;124;137 112;115;125;138 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. We found that over-expression of BBLF2/3 had no effect on the level of the late protein, FR3, induced by wt ZEBRA, Z(S173A) or Z(Y180E). 2010 PLoS pathogens Result EBV S173A;Y180E 117;129 122;134 BZLF1;BZLF1;BZLF1 108;115;127 113;116;128 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. We found that Z(Y180E) and Z(K188A) were two-to three-fold defective in interacting both with Rp and with oriLyt when compared to the wild type protein. 2010 PLoS pathogens Result EBV Y180E;K188A 16;29 21;34 BZLF1;BZLF1 14;27 15;28 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. While co-expression of all six replication proteins with Z(S173A) induced late gene expression to 33.4 and 35.4% that of wt ZEBRA. 2010 PLoS pathogens Result EBV S173A 59 64 BZLF1;BZLF1 124;57 129;58 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. Z(F193E) was slightly impaired and resulted in a less intense ladder than wt ZEBRA. 2010 PLoS pathogens Result EBV F193E 2 7 BZLF1;BZLF1 77;0 82;1 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. Z(K188A) served as a typical ZEBRA RD mutant; the mutant Z(F193E) was partially defective in induction of late genes and DNA replication. 2010 PLoS pathogens Result EBV K188A;F193E 2;59 7;64 BZLF1;BZLF1;BZLF1 29;0;57 34;1;58 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. Z(S173A) was the least defective while Z(K188A) was the most impaired. 2010 PLoS pathogens Result EBV S173A;K188A 2;41 7;46 BZLF1;BZLF1 0;39 1;40 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. Z(Y180E) precipitated 3 times more oriLyt in the presence replication proteins; Z(S173A), 1.8-fold, and wild type ZEBRA 1.6-fold. 2010 PLoS pathogens Result EBV Y180E;S173A 2;82 7;87 BZLF1;BZLF1;BZLF1 114;0;80 119;1;81 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. Z(Y180E) shifted between 0.1% and 0.7% depending on the probe used in the shift assay; Z(K188A), 1% to 9.2%, and wt ZEBRA, 23.4% to 46%. 2010 PLoS pathogens Result EBV Y180E;K188A 2;89 7;94 BZLF1;BZLF1;BZLF1 116;0;87 121;1;88 20849661 Conserved mutation of Epstein-Barr virus-encoded BamHI-A Rightward Frame-1 (BARF1) gene in Indonesian nasopharyngeal carcinoma. At the protein level most NPC (78.6%) demonstrated 2 amino acid substitutions at position V29A (valine to alanine) and H130R (histidine to arginine), except 1 sample (NPC-13) which displayed a unique conversion in the position of W72G and H130R. 2010 Infectious agents and cancer Result EBV V29A;H130R;W72G;H130R 90;119;230;239 94;124;234;244 Nasopharyngeal carcinoma;Nasopharyngeal carcinoma 26;167 29;170 20849661 Conserved mutation of Epstein-Barr virus-encoded BamHI-A Rightward Frame-1 (BARF1) gene in Indonesian nasopharyngeal carcinoma. One NPC (NPC-20) and 3 PTLD isolates (PTLD-2, PTLD-6, and PTLD-7) were put in a separated branch from other isolates revealing same codon conversions (V29A and H130R) because they had less overall nucleotide mutations. 2010 Infectious agents and cancer Result EBV V29A;H130R 151;160 155;165 Lymphoproliferative disease;Lymphoproliferative disease;Lymphoproliferative disease;Nasopharyngeal carcinoma;Nasopharyngeal carcinoma 38;46;58;4;9 42;50;62;7;12 20849661 Conserved mutation of Epstein-Barr virus-encoded BamHI-A Rightward Frame-1 (BARF1) gene in Indonesian nasopharyngeal carcinoma. Some isolates (14.3%) showed rare mutations at position W72G (tryptophan to glycine). 2010 Infectious agents and cancer Result EBV W72G 56 60 20849661 Conserved mutation of Epstein-Barr virus-encoded BamHI-A Rightward Frame-1 (BARF1) gene in Indonesian nasopharyngeal carcinoma. The BARF1 used for analysis contained the most prevalent V29A and H130R. 2010 Infectious agents and cancer Result EBV V29A;H130R 57;66 61;71 BARF1 4 9 20849661 Conserved mutation of Epstein-Barr virus-encoded BamHI-A Rightward Frame-1 (BARF1) gene in Indonesian nasopharyngeal carcinoma. The C15 tumor line displayed 4 nucleotide mutations, one at position of 165589 (T to C) leading to V29A conversion, and 3 silent mutations at position of 165677 (G to A), 165944 (C to T), and 166136 (C to T). 2010 Infectious agents and cancer Result EBV V29A;T165589C;G165677A;C165944T;C166136T 99;72;154;171;192 103;87;169;186;207 20849661 Conserved mutation of Epstein-Barr virus-encoded BamHI-A Rightward Frame-1 (BARF1) gene in Indonesian nasopharyngeal carcinoma. The C666-1 cell line showed 1 silent mutation at position of 165545 (T to C). 2010 Infectious agents and cancer Result EBV T165545C 61 76 20849661 Conserved mutation of Epstein-Barr virus-encoded BamHI-A Rightward Frame-1 (BARF1) gene in Indonesian nasopharyngeal carcinoma. The conserved V29A mutation is positioned at the start of an internal beta-sheet element and is predicted to render little change to the overall structure. 2010 Infectious agents and cancer Result EBV V29A 14 18 20849661 Conserved mutation of Epstein-Barr virus-encoded BamHI-A Rightward Frame-1 (BARF1) gene in Indonesian nasopharyngeal carcinoma. The H130R replacement is located towards the water-contact surface of the inner core of the BARF1 hexameric structure and may have little effect on structure, merely affecting hydrophilic water interactions. 2010 Infectious agents and cancer Result EBV H130R 4 9 BARF1 92 97 20849661 Conserved mutation of Epstein-Barr virus-encoded BamHI-A Rightward Frame-1 (BARF1) gene in Indonesian nasopharyngeal carcinoma. The W29G mutation is providing more flexibility to a beta sheet element inside the BARF1 molecule normally stabilized by hydrophobic interactions. 2010 Infectious agents and cancer Result EBV W29G 4 8 BARF1 83 88 20849661 Conserved mutation of Epstein-Barr virus-encoded BamHI-A Rightward Frame-1 (BARF1) gene in Indonesian nasopharyngeal carcinoma. These converting amino acids were identical to those of NPC majority (V29A and H130R). 2010 Infectious agents and cancer Result EBV V29A;H130R 70;79 74;84 Nasopharyngeal carcinoma 56 59 20849661 Conserved mutation of Epstein-Barr virus-encoded BamHI-A Rightward Frame-1 (BARF1) gene in Indonesian nasopharyngeal carcinoma. Very rare mutations at position S12T (serine to threonine) and S128F (serine to phenylalanine) were also observed in 2 single NPC samples, together with the above-mentioned more prevalent V29A and H130R changes. 2010 Infectious agents and cancer Result EBV S12T;S128F;V29A;H130R 32;63;188;197 36;68;192;202 Nasopharyngeal carcinoma 126 129 21440926 Epstein-Barr virus nuclear protein 3C binds to the N-terminal (NTD) and beta trefoil domains (BTD) of RBP/CSL; only the NTD interaction is essential for lymphoblastoid cell growth. EBNA3C binding to the beta trefoil domain containing constructs (B and B+C) was eliminated by W227S mutation, confirming the role of this motif as a Notch RAM-like interaction sequence in yeast. 2011 Virology Result EBV W227S 94 99 EBNA3C 0 6 21440926 Epstein-Barr virus nuclear protein 3C binds to the N-terminal (NTD) and beta trefoil domains (BTD) of RBP/CSL; only the NTD interaction is essential for lymphoblastoid cell growth. Expressed as a GST fusion protein in bacteria, EBNA3C aa164-366 bound RBP/CSL, while EBNA3C aa164-366 W227S was deficient in RBP/CSL binding, despite equal expression levels (Fig 3C). 2011 Virology Result EBV W227S 102 107 EBNA3C;EBNA3C 47;85 53;91 21440926 Epstein-Barr virus nuclear protein 3C binds to the N-terminal (NTD) and beta trefoil domains (BTD) of RBP/CSL; only the NTD interaction is essential for lymphoblastoid cell growth. GST-EBNA3C aa164-366 efficiently retrieved RBP/CSL from 293T lysates and N-terminal deletion of GST-EBNA3C to aa184 or aa211 reduced, but did not eliminate RBP/CSL binding, while further deletion to aa230 resulted in a loss of association (Fig 3A). 2011 Virology Result EBV del aa164-366;del aa184;del aa211;del aa230 11;110;119;199 20;115;124;204 EBNA3C;EBNA3C 4;100 10;106 21440926 Epstein-Barr virus nuclear protein 3C binds to the N-terminal (NTD) and beta trefoil domains (BTD) of RBP/CSL; only the NTD interaction is essential for lymphoblastoid cell growth. Importantly, EBNA3C HDmut plus W227S had only weak residual binding to full length RBP/CSL. 2011 Virology Result EBV W227S 31 36 EBNA3C 13 19 21440926 Epstein-Barr virus nuclear protein 3C binds to the N-terminal (NTD) and beta trefoil domains (BTD) of RBP/CSL; only the NTD interaction is essential for lymphoblastoid cell growth. In mammalian cells however, EBNA3C W227S binding to RBP/CSL was comparable to EBNA3C wild-type or 209TFGC AAAA (HDmut) (Fig 4A). 2011 Virology Result EBV W227S 35 40 EBNA3C;EBNA3C 28;78 34;84 21440926 Epstein-Barr virus nuclear protein 3C binds to the N-terminal (NTD) and beta trefoil domains (BTD) of RBP/CSL; only the NTD interaction is essential for lymphoblastoid cell growth. In reporter gene assays, EBNA3C W227S was equivalent to EBNA3C wild-type in repressing EBNA2 activation of Cp through RBP/CSL (Fig 5A), whereas EBNA3C Delta182-231 and HDmut have been previously shown to be defective in repression of EBNA2 activation of Cp. 2011 Virology Result EBV W227S 32 37 EBNA3C;EBNA3C;EBNA3C;EBNA2;EBNA2 25;56;144;87;234 31;62;150;92;239 21440926 Epstein-Barr virus nuclear protein 3C binds to the N-terminal (NTD) and beta trefoil domains (BTD) of RBP/CSL; only the NTD interaction is essential for lymphoblastoid cell growth. Only the EBNA3C double mutant (HDmut + W227S) failed to bind RBP/CSL. 2011 Virology Result EBV W227S 39 44 EBNA3C 9 15 21440926 Epstein-Barr virus nuclear protein 3C binds to the N-terminal (NTD) and beta trefoil domains (BTD) of RBP/CSL; only the NTD interaction is essential for lymphoblastoid cell growth. The EBNA3C W227S was further assessed using the EBNA3C-HT LCL transcomplementation assay in which the ability of EBNA3C mutants to maintain growth is determined following EBNA3C-HT inactivation by withdrawal of 4HT from the media. 2011 Virology Result EBV W227S 11 16 EBNA3C;EBNA3C;EBNA3C;EBNA3C 4;48;113;171 10;54;119;177 21440926 Epstein-Barr virus nuclear protein 3C binds to the N-terminal (NTD) and beta trefoil domains (BTD) of RBP/CSL; only the NTD interaction is essential for lymphoblastoid cell growth. The potential role of the 227WTP sequence in mediating EBNA3C binding to RBP/CSL was evaluated with a W227S mutation. 2011 Virology Result EBV W227S 102 107 EBNA3C 55 61 21440926 Epstein-Barr virus nuclear protein 3C binds to the N-terminal (NTD) and beta trefoil domains (BTD) of RBP/CSL; only the NTD interaction is essential for lymphoblastoid cell growth. To assess the significance of WTP mediated binding for EBNA3C function, the effect of the W227S mutation on EBNA3C's ability to repress EBNA2 and support LCL proliferation was investigated. 2011 Virology Result EBV W227S 90 95 EBNA3C;EBNA3C;EBNA2 55;108;136 61;114;141 21440926 Epstein-Barr virus nuclear protein 3C binds to the N-terminal (NTD) and beta trefoil domains (BTD) of RBP/CSL; only the NTD interaction is essential for lymphoblastoid cell growth. Western blotting for EBNA3C and EBNA3C W227S found equivalent levels at 0 and 40 days after 4HT withdrawal, making it unlikely that reduced binding to RBP/CSL was overcome by selection for increased levels of EBNA3C W227S expression. 2011 Virology Result EBV W227S;W227S 39;216 44;221 EBNA3C;EBNA3C;EBNA3C 21;32;209 27;38;215 21440926 Epstein-Barr virus nuclear protein 3C binds to the N-terminal (NTD) and beta trefoil domains (BTD) of RBP/CSL; only the NTD interaction is essential for lymphoblastoid cell growth. When complemented with wild-type EBNA3C or EBNA3C W227S expressed from oriP plasmids, cells continued to grow at a rate comparable to growth in the presence of 4HT. 2011 Virology Result EBV W227S 50 55 EBNA3C;EBNA3C 33;43 39;49 21560118 Transmembrane peptides used to investigate the homo-oligomeric interface and binding hotspot of latent membrane protein 1. A population-based transcriptional reporter assay in HEp2 cells (Figure 6C) was used to determine if the D150A mutation attenuates LMP-1 activation of the NFkappaB pathway. 2011 Biopolymers Result EBV D150A 105 110 LMP1 131 136 21560118 Transmembrane peptides used to investigate the homo-oligomeric interface and binding hotspot of latent membrane protein 1. Because amino acid substitutions can perturb protein stability and folding, the subcellular localization of LMP-1 and LMP-1 D150A in HEp2 cells was compared to ensure that the D150A substitution did not affect LMP-1 folding or subcellular localization. 2011 Biopolymers Result EBV D150A;D150A 124;176 129;181 LMP1;LMP1;LMP1 108;118;210 113;123;215 21560118 Transmembrane peptides used to investigate the homo-oligomeric interface and binding hotspot of latent membrane protein 1. By contrast, TM5 D150A is mostly dimeric with no detectable trimeric species (Figure 3F). 2011 Biopolymers Result EBV D150A 17 22 21560118 Transmembrane peptides used to investigate the homo-oligomeric interface and binding hotspot of latent membrane protein 1. Expression vectors encoding LMP-1 with an aspartic acid to alanine substitution at position 150 (LMP-1 D150A) were constructed for this purpose. 2011 Biopolymers Result EBV D150A;D150A 103;42 108;95 LMP1;LMP1 28;97 33;102 21560118 Transmembrane peptides used to investigate the homo-oligomeric interface and binding hotspot of latent membrane protein 1. Fluorescence quenching analysis confirmed the altered self-association of TM5 D150A; TM5 D150A rapidly dissociated upon dilution in detergent in a manner analogous to TM1 (Figure 2E). 2011 Biopolymers Result EBV D150A;D150A 78;89 83;94 21560118 Transmembrane peptides used to investigate the homo-oligomeric interface and binding hotspot of latent membrane protein 1. From these results we conclude that D150 drives TM5 trimerization and the substitution of an alanine for the aspartic acid at position 150 does not disrupt but alters the TM5 oligomeric complex. 2011 Biopolymers Result EBV D150A 93 138 21560118 Transmembrane peptides used to investigate the homo-oligomeric interface and binding hotspot of latent membrane protein 1. HEp2 cells were transfected with LMP-1 or LMP-1 D150A mutant expression vectors and the ratio of nuclear/cytoplasmic distribution of p65 was quantified later in single cells by immunofluorescence intensity. 2011 Biopolymers Result EBV D150A 48 53 LMP1;LMP1 33;42 38;47 21560118 Transmembrane peptides used to investigate the homo-oligomeric interface and binding hotspot of latent membrane protein 1. LMP-1 D150A expressing cells accumulated 1.2 times more luciferase than empty vector transfected cells and approximately six-fold less than cells expressing LMP-1. 2011 Biopolymers Result EBV D150A 6 11 LMP1;LMP1 0;157 5;162 21560118 Transmembrane peptides used to investigate the homo-oligomeric interface and binding hotspot of latent membrane protein 1. LMP-1, lyLMP-1 (non-functional truncation variant of LMP-1 encoded by Epstein-Barr Virus) and LMP-1 D150A expression levels were analyzed by Western blot analysis (Figure 6D). 2011 Biopolymers Result EBV D150A 100 105 LMP1;LMP1;LMP1 0;53;94 5;58;99 21560118 Transmembrane peptides used to investigate the homo-oligomeric interface and binding hotspot of latent membrane protein 1. Localization of LMP-1 D150A (Figure 6B) was indistinguishable from wild type LMP-1. 2011 Biopolymers Result EBV D150A 22 27 LMP1;LMP1 16;77 21;82 21560118 Transmembrane peptides used to investigate the homo-oligomeric interface and binding hotspot of latent membrane protein 1. Migration of TM5 and TM5 D150A was assessed by SDS-PAGE (Figure 2D and Supporting Information Figure 1B). 2011 Biopolymers Result EBV D150A 25 30 21560118 Transmembrane peptides used to investigate the homo-oligomeric interface and binding hotspot of latent membrane protein 1. Normalized luciferase levels (relative light units/LMP-1 protein) in LMP-1 D150A and lyLMP-1 expressing cells were ~15% those in LMP-1 expressing cells (Supporting Information Figure 4). 2011 Biopolymers Result EBV D150A 75 80 LMP1;LMP1;LMP1 51;69;129 56;74;134 21560118 Transmembrane peptides used to investigate the homo-oligomeric interface and binding hotspot of latent membrane protein 1. Of the subpopulation of cells with predominately nuclear p65 (nuclear/cytoplasmic ratio > 1), the ratio of nuclear to cytoplasmic p65 in LMP-1 expressing cells was 2.8 whereas this ratio was 1.6 in the analogous subpopulation of cells expressing LMP-1 D150A (Table 1 and Figure 7C), a significant difference suggesting that D150 plays important roles in the p65 translocation. 2011 Biopolymers Result EBV D150A 252 257 LMP1;LMP1 137;246 142;251 21560118 Transmembrane peptides used to investigate the homo-oligomeric interface and binding hotspot of latent membrane protein 1. SE AUC was used to investigate the stoichiometry of TM1, TM5 and TM5 D150A peptides, solubilized in C14-betaine buffer with 21% deuterium (Figure 3). 2011 Biopolymers Result EBV D150A 69 74 21560118 Transmembrane peptides used to investigate the homo-oligomeric interface and binding hotspot of latent membrane protein 1. The majority of LMP-1 negative cells in each transfected population (those cells that contained no detectable immunoreactive LMP-1, lyLMP-1 or LMP-1 D150A) contained <=14% nuclear p65. 2011 Biopolymers Result EBV D150A 149 154 LMP1;LMP1;LMP1 16;125;143 21;130;148 21560118 Transmembrane peptides used to investigate the homo-oligomeric interface and binding hotspot of latent membrane protein 1. The number of LMP-1 D150A expressing cells with predominantly nuclear p65 was significantly less than that observed in wild type LMP-1 expressing cells (38% versus 78%, respectively). 2011 Biopolymers Result EBV D150A 20 25 LMP1;LMP1 14;129 19;134 21560118 Transmembrane peptides used to investigate the homo-oligomeric interface and binding hotspot of latent membrane protein 1. The oligomerization of TM1, TM5 and TM5 D150A was compared by ToxR assay (Figure 4B). 2011 Biopolymers Result EBV D150A 40 45 21560118 Transmembrane peptides used to investigate the homo-oligomeric interface and binding hotspot of latent membrane protein 1. Therefore, the ability of wild type LMP-1 and LMP-1 D150A to promote p65 translocation to the nucleus was evaluated in single cells (Figure 7A). 2011 Biopolymers Result EBV D150A 52 57 LMP1;LMP1 36;46 41;51 21560118 Transmembrane peptides used to investigate the homo-oligomeric interface and binding hotspot of latent membrane protein 1. Therefore, the decreased NFkappaB activity in LMP-1 D150A expressing cells could be the result of two different phenomena: cells expressing LMP-1 D150A are either impaired in their ability to activate NFkappaB, or fewer of these cells have the capacity to stimulate NFkappaB. 2011 Biopolymers Result EBV D150A;D150A 52;146 57;151 LMP1;LMP1 46;140 51;145 21560118 Transmembrane peptides used to investigate the homo-oligomeric interface and binding hotspot of latent membrane protein 1. Therefore, to determine the impact of the D150A substitution on LMP-1 oligomerization, the ability of LMP-1 D150A to signal was compared to that of wild type LMP-1. 2011 Biopolymers Result EBV D150A;D150A 42;108 47;113 LMP1;LMP1;LMP1 64;102;158 69;107;163 21560118 Transmembrane peptides used to investigate the homo-oligomeric interface and binding hotspot of latent membrane protein 1. These results complement the NFkappaB luciferase assay results and confirm that LMP-1 D150A is compromised in its ability to signal to NFkappaB. 2011 Biopolymers Result EBV D150A 86 91 LMP1 80 85 21560118 Transmembrane peptides used to investigate the homo-oligomeric interface and binding hotspot of latent membrane protein 1. These results indicate that substitution of D150 with alanine has no detectable effect on the subcellular localization of LMP-1, suggesting that LMP-1 D150A is properly folded and trafficked in cells. 2011 Biopolymers Result EBV D150A 151 156 LMP1;LMP1 122;145 127;150 21560118 Transmembrane peptides used to investigate the homo-oligomeric interface and binding hotspot of latent membrane protein 1. Thus, LMP-1 D150A is deficient in its ability to activate NFkappaB in HEp2 cells. 2011 Biopolymers Result EBV D150A 12 17 LMP1 6 11 21560118 Transmembrane peptides used to investigate the homo-oligomeric interface and binding hotspot of latent membrane protein 1. TM5 D150A migrated faster than wild type TM5, with an apparent molecular weight similar to that of the other LMP-1 TMs. 2011 Biopolymers Result EBV D150A 4 9 LMP1 109 114 21560118 Transmembrane peptides used to investigate the homo-oligomeric interface and binding hotspot of latent membrane protein 1. TM5 D150A was impaired in its ability to oligomerize in comparison with wild-type TM5. 2011 Biopolymers Result EBV D150A 4 9 21560118 Transmembrane peptides used to investigate the homo-oligomeric interface and binding hotspot of latent membrane protein 1. To distinguish between these possibilities, the NFkappaB activity of single cells expressing LMP-1 was compared to cells expressing LMP-1 D150A. 2011 Biopolymers Result EBV D150A 138 143 LMP1;LMP1 93;132 98;137 21560118 Transmembrane peptides used to investigate the homo-oligomeric interface and binding hotspot of latent membrane protein 1. To test the impact of D150 on the self-association of TM5, we compared the behavior of TM5 to that of a TM5 peptide with an alanine in place of the aspartic acid (TM5 D150A). 2011 Biopolymers Result EBV D150A 167 172 21560118 Transmembrane peptides used to investigate the homo-oligomeric interface and binding hotspot of latent membrane protein 1. To this end, cell-based functional assays were used to evaluate the effect of the TM5 D150A mutation on the function of full-length LMP-1. 2011 Biopolymers Result EBV D150A 86 91 LMP1 132 137 21560118 Transmembrane peptides used to investigate the homo-oligomeric interface and binding hotspot of latent membrane protein 1. When compared to cells expressing wild-type LMP-1, fewer LMP-1 D150A expressing cells have predominantly nuclear p65, and in those LMP-1 D150A expressing cells that do have a nuclear/cytoplasmic p65 ratio >1, less p65 has translocated to the nucleus as compared to LMP-1 expressing cells with a nuclear/cytoplasmic ratio >1. 2011 Biopolymers Result EBV D150A;D150A 63;137 68;142 LMP1;LMP1;LMP1;LMP1 44;57;131;265 49;62;136;270 22348267 Sequence analysis of Epstein-Barr virus EBNA-2 gene coding amino acid 148-487 in nasopharyngeal and gastric carcinomas. Among the 20 loci with nucleotide changes, three nucleotide mutations (g48991t, c48998a and t49613a) were detected in all the EBVaGC, NPC and TW samples (113/113, 100%) (Figure 1). 2012 Virology journal Result EBV G48991T;C48998A;T49613A 71;80;92 78;87;99 Nasopharyngeal carcinoma;Gastric carcinoma 134;126 137;132 22348267 Sequence analysis of Epstein-Barr virus EBNA-2 gene coding amino acid 148-487 in nasopharyngeal and gastric carcinomas. Interestingly, the four silent mutations and five non-silent mutations (R413G, I438L, E476G, P484H and I486T) in this subtype were only detected in 12 NPC samples. 2012 Virology journal Result EBV R413G;I438L;E476G;P484H;I486T 72;79;86;93;103 77;84;91;98;108 Nasopharyngeal carcinoma 151 154 22348267 Sequence analysis of Epstein-Barr virus EBNA-2 gene coding amino acid 148-487 in nasopharyngeal and gastric carcinomas. Interestingly, the mutations in TAD residue (I438L) and the NLS residues (E476G, P484H and I486T) were only detected in NPC samples which located in the carboxyl terminus of EBNA-2 gene. 2012 Virology journal Result EBV I438L;E476G;P484H;I486T 45;74;81;91 50;79;86;96 EBNA2 174 180 Nasopharyngeal carcinoma 120 123 22348267 Sequence analysis of Epstein-Barr virus EBNA-2 gene coding amino acid 148-487 in nasopharyngeal and gastric carcinomas. Residue P291T were present in 6 NPC samples and the residue R413G was detected only in TW392. 2012 Virology journal Result EBV P291T;R413G 8;60 13;65 Nasopharyngeal carcinoma 32 35 22348267 Sequence analysis of Epstein-Barr virus EBNA-2 gene coding amino acid 148-487 in nasopharyngeal and gastric carcinomas. The mutation at residue R163M was detected in all samples in the self-association domain. 2012 Virology journal Result EBV R163M 24 29 22348267 Sequence analysis of Epstein-Barr virus EBNA-2 gene coding amino acid 148-487 in nasopharyngeal and gastric carcinomas. The residue P291T mutation existed in 6 NPC samples (Figure 1). 2012 Virology journal Result EBV P291T 12 17 Nasopharyngeal carcinoma 40 43 22348267 Sequence analysis of Epstein-Barr virus EBNA-2 gene coding amino acid 148-487 in nasopharyngeal and gastric carcinomas. This type had six non-silent mutations (P291T, R413G, I438L, E476G, P484H and I486T) and four silent mutations (383cct-cca, 408gcc-gca, 417acg-aca and 470tca-tct) in addition to the three common mutations (Figure 1). 2012 Virology journal Result EBV P291T;R413G;I438L;E476G;P484H;I486T 40;47;54;61;68;78 45;52;59;66;73;83 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. All variants from the second group are characterized by F144I, D150A and L151I and are more closely affiliated to the China1 strain described by Edwards et al. 2012 PloS one Result EBV F144I;D150A;L151I 56;63;73 61;68;78 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. As shown above, F144 I is the determinant of the second group of variants. 2012 PloS one Result EBV F144I 16 22 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. By sequence comparisons and directed mutagenesis we identified I124V as the amino acid change responsible for enhanced NF-kappaB activation of a variant of the first group, 7825 (Figure S4A). 2012 PloS one Result EBV I124V 63 68 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. F106Y is present in 31/31 variants. 2012 PloS one Result EBV F106Y 0 5 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. F144I/D150A/L150I was found in 41.5% of HIV-HL and in 31.8% of participants without tumor. 2012 PloS one Result EBV L150I;F144I;D150A 12;0;6 17;5;11 Hodgkin lymphoma 40 46 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. Finally, we found that F106Y leads to increased NF-kappaB activation in the context of variants 7795, 7815, 7918, 7948 and 7821 of the third group (Figure S4B). 2012 PloS one Result EBV F106Y 23 28 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. Four polymorphisms L29V, V43L, D46N and I68L are unique to A2 and three, I137L, L178M and E328A, are unique to CAO, which also contains two additional direct repeats (Figure S2). 2012 PloS one Result EBV L29V;V43L;D46N;I68L;I137L;L178M;E328A 19;25;31;40;73;80;90 23;29;35;44;78;85;95 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. Functional analysis of LMP1 mutants shows that mutation F144I leads to a significant increase in NF-kappaB activation (Figure 2E and Table S1). 2012 PloS one Result EBV F144I 56 61 LMP1 23 27 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. I124V/I152L was found in 12.2% of HIV-HL and in 24.7% of participants without tumor. 2012 PloS one Result EBV I152L;I124V 6;0 11;5 Hodgkin lymphoma 34 40 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. In contrast, mutation of tyrosine 106 to phenylalanine in variant A2 does not change NF-kappaB signaling potential of the variant, which was likely to be due to other polymorphisms regulating this effect. 2012 PloS one Result EBV Y106F 25 54 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. In contrast, other mutations are slightly deleterious (M129I, D150A or L151I) or neutral (Q189P, S192T and G212S). 2012 PloS one Result EBV M129I;D150A;L151I;Q189P;S192T;G212S 55;62;71;90;97;107 60;67;76;95;102;112 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. In order to confirm the importance of F144I we mutated isoleucine 144 to phenylalanine in variant A2. 2012 PloS one Result EBV F144I;I144F 38;55 43;86 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. In summary, we found two phylogenetic groups of LMP1 in which all variants have increased ability to activate NF-kappaB when compared to B95-8 LMP1 and described I124V for the first group and F144I for the second group as polymorphisms involved in the increased NF-kappaB activation. 2012 PloS one Result EBV I124V;F144I 162;192 167;197 LMP1;LMP1 48;143 52;147 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. Interestingly, the single mutation F106Y in the context of B95-8 increases NF-kappaB activation level 3-fold, whereas in the context of chimeras P1118/B95-8 and A2118/B95-8 its effect is limited indicating that other polymorphisms located between amino acids 1 and 118 counteract this effect. 2012 PloS one Result EBV F106Y 35 40 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. Mutation F106Y, but not I85L, is associated with an increase in NF-kappaB activation level (Figure 2E and Table S1). 2012 PloS one Result EBV F106Y;I85L 9;24 14;28 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. NF-kappaB activation level induced by A2 I144F is close to that of B95-8 (Figure 2F and Table S1). 2012 PloS one Result EBV I144F 41 46 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. Our results showed that I124V/I152L and F144I/D150A/L151I are not associated with HL development neither in the simple and nor in the multivariable analyses. 2012 PloS one Result EBV I124V;I152L;F144I;D150A;L151I 24;30;40;46;52 29;35;45;51;57 Hodgkin lymphoma 82 84 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. Polymorphism F144I modulates NF-kappaB activation mediated by variant A2. 2012 PloS one Result EBV F144I 13 18 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. Polymorphisms I124V/I152L and F144I/D150A/L151I always segregating together were used to represent the two phylogenetic groups, respectively. 2012 PloS one Result EBV I124V;I152L;F144I;D150A;L151I 14;20;30;36;42 19;25;35;41;47 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. Polymorphisms I124V/I152L and F144I/D150A/L151I are not associated with HIV-HL. 2012 PloS one Result EBV I124V;I152L;F144I;D150A;L151I 14;20;30;36;42 19;25;35;41;47 Hodgkin lymphoma 72 78 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. Since we have previously shown that this polymorphism has no influence in the context of A2 LMP1 (Figure 2F) and is present in all LMP1 variants sequences obtained in this study (Figure 1D and 3A), the effect of F106Y is modulated by sequence variations. 2012 PloS one Result EBV F106Y 212 217 LMP1;LMP1 92;131 96;135 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. The comparison of the amino acid sequences of variants P1 and A2 within residues 1 to 118 shows two common polymorphisms: I85L and F106Y (Figure 1D), which were introduced individually in the B95-8 sequence to evaluate their influence. 2012 PloS one Result EBV I85L;F106Y 122;131 126;136 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. The distribution of F144I is more restricted (5/31). 2012 PloS one Result EBV F144I 20 25 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. The first group comprising 5 LMP1 variants - 7836, 7885, 7850, 7825 and 7939- is characterized by two polymorphisms I124V and I152L, which always segregate together. 2012 PloS one Result EBV I124V;I152L 116;126 121;131 LMP1 29 33 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. These results demonstrate that F144I is the unique polymorphism responsible for the high NF-kappaB activation level mediated by A2. 2012 PloS one Result EBV F144I 31 36 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. To better understand the importance of polymorphism F144I in the context of LMP1 sequence variation in individuals without a diagnosis of EBV-associated tumor we characterized LMP1 from blood of HIV-infected individuals included in the SHCS. 2012 PloS one Result EBV F144I 52 57 LMP1;LMP1 76;176 80;180 EBV-HIV coinfections 195 207 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. We assessed the presence of polymorphisms I124V/I152L and F144I/D150A/L150I for each participant's sample (Table 1). 2012 PloS one Result EBV I152L;I124V;L150I;F144I;D150A 48;42;70;58;64 53;47;75;63;69 22590638 Genomic sequencing and comparative analysis of Epstein-Barr virus genome isolated from primary nasopharyngeal carcinoma biopsy. Although no mutations were identified in known and predicted TATA boxes, sequence changes of 11,324 G>T and 11,404 C>T in Cp, and 49,937 G>A and 50,134 G>C in Qp were observed. 2012 PloS one Result EBV G11324T;C11404T;G49937A;G50134C 93;108;130;145 103;118;140;155 22590638 Genomic sequencing and comparative analysis of Epstein-Barr virus genome isolated from primary nasopharyngeal carcinoma biopsy. Based on strain-determining amino acids of EBNA1 (A487V, D499E and T524I) and C-terminus of LMP1 (G212S, Q334R, L338S), HKNPC1 can be classified into the V-val and China 1 genotypes. 2012 PloS one Result EBV A487V;D499E;T524I;G212S;Q334R;L338S 50;57;67;98;105;112 55;62;72;103;110;117 EBNA1;LMP1 43;92 48;96 22590638 Genomic sequencing and comparative analysis of Epstein-Barr virus genome isolated from primary nasopharyngeal carcinoma biopsy. Genes encoded for microRNAs BHRF1 (miR-BHRF1-1 to -3) and EBER1 are highly conserved with no variations among the five strains, whereas in the miR-BARTs, only a single point mutation (147,821 T>A) was observed in the sequence encoding miR-BART19-5p. 2012 PloS one Result EBV T147821A 184 195 BHRF1;BHRF1 28;39 33;44 22590638 Genomic sequencing and comparative analysis of Epstein-Barr virus genome isolated from primary nasopharyngeal carcinoma biopsy. Variations were observed in EBER2, however, only one point mutation (7,048 A>C) is shared by GD2 and HKNPC1, and other mutations are not exclusive to NPC-derived strains. 2012 PloS one Result EBV A7048C 69 78 Nasopharyngeal carcinoma 150 153 24016332 Identification of a novel variant of LMP-1 of EBV in patients with endemic Burkitt lymphoma in western Kenya. The atypical K variant containing H352R was found in 6 (16.2%) eBL sequences and 4 (16.7%) healthy controls (p=1.00, OR 0.97, 95% CI 0.24-3.87). 2013 Infectious agents and cancer Result EBV H352R 34 39 Burkitt lymphoma 63 66 24016332 Identification of a novel variant of LMP-1 of EBV in patients with endemic Burkitt lymphoma in western Kenya. The G318K mutation was highly linked to the Q322E mutation, such that all 22 sequences observed containing G318K also contained Q322E. 2013 Infectious agents and cancer Result EBV G318K;Q322E;G318K;Q322E 4;44;107;128 9;49;112;133 24016332 Identification of a novel variant of LMP-1 of EBV in patients with endemic Burkitt lymphoma in western Kenya. This variant always differed from the B95.8 sequence at 5 amino acids: G318K, Q322E, Q334R, L338S, and S366T; and was frequently found with H352R (52.4%). 2013 Infectious agents and cancer Result EBV G318K;Q322E;Q334R;L338S;S366T;H352R 71;78;85;92;103;140 76;83;90;97;108;145 24705134 Nuclear translocation and regulation of intranuclear distribution of cytoplasmic poly(A)-binding protein are distinct processes mediated by two Epstein Barr virus proteins. 293 cells transfected with empty vector, or expression vectors for BGLF5, WT ZEBRA, Z(N182K), or Z(S186E) were analyzed for new protein synthesis. 2014 PloS one Result EBV N182K;S186E 86;99 91;104 BGLF5;BZLF1;BZLF1;BZLF1 67;77;84;97 72;82;85;98 24705134 Nuclear translocation and regulation of intranuclear distribution of cytoplasmic poly(A)-binding protein are distinct processes mediated by two Epstein Barr virus proteins. A ZEBRA mutant, Z(R183E), which induces nuclear aggregates and is concentrated in nuclear aggresomes, colocalized with PABPC within the nuclear aggregates and aggresomes when transfected in the absence of BGLF5. 2014 PloS one Result EBV R183E 18 23 BGLF5;BZLF1;BZLF1 205;2;16 210;7;17 24705134 Nuclear translocation and regulation of intranuclear distribution of cytoplasmic poly(A)-binding protein are distinct processes mediated by two Epstein Barr virus proteins. Although Z(S186A) efficiently binds to three ZREs, ZRE-R1, ZIIIA, and ZIIIB, as well as the AP-1 octamer site, this mutant is deficient in binding to methylated ZRE-R3 in the promoter of the EBV gene encoding Rta. 2014 PloS one Result EBV S186A 11 16 BRLF1;BZLF1 209;9 212;10 24705134 Nuclear translocation and regulation of intranuclear distribution of cytoplasmic poly(A)-binding protein are distinct processes mediated by two Epstein Barr virus proteins. Cell counts (Table 2) showed no significant decrease in PABPC translocation by Z(N182K) (58.6% of 133 cells) or by Z(S186A) (65.6% of 131 cells) compared to WT ZEBRA (60.9% of 174 cells). 2014 PloS one Result EBV N182K;S186A 81;117 86;122 BZLF1;BZLF1;BZLF1 160;79;115 165;80;116 24705134 Nuclear translocation and regulation of intranuclear distribution of cytoplasmic poly(A)-binding protein are distinct processes mediated by two Epstein Barr virus proteins. In contrast, Z(S186E), which was defective for PABPC translocation. 2014 PloS one Result EBV S186E 15 20 BZLF1 13 14 24705134 Nuclear translocation and regulation of intranuclear distribution of cytoplasmic poly(A)-binding protein are distinct processes mediated by two Epstein Barr virus proteins. In contrast, ZEBRA mutant Z(S186E). 2014 PloS one Result EBV S186E 28 33 BZLF1;BZLF1 13;26 18;27 24705134 Nuclear translocation and regulation of intranuclear distribution of cytoplasmic poly(A)-binding protein are distinct processes mediated by two Epstein Barr virus proteins. Some clumping of the Z(N182K) mutant was seen. 2014 PloS one Result EBV N182K 23 28 BZLF1 21 22 24705134 Nuclear translocation and regulation of intranuclear distribution of cytoplasmic poly(A)-binding protein are distinct processes mediated by two Epstein Barr virus proteins. The inability of Z(S186E) to translocate PABPC and its ability to efficiently direct the intranuclear distribution of PABPC indicates that these two functions of ZEBRA are distinct. 2014 PloS one Result EBV S186E 19 24 BZLF1;BZLF1 162;17 167;18 24705134 Nuclear translocation and regulation of intranuclear distribution of cytoplasmic poly(A)-binding protein are distinct processes mediated by two Epstein Barr virus proteins. The mutant Z(N182K) conferred a diffuse yet uneven distribution pattern upon PABPC; this distribution was distinct from the uniformly diffuse distribution seen with WT ZEBRA, and was clearly different from the high degree of clumping seen with BGLF5. 2014 PloS one Result EBV N182K 13 18 BGLF5;BZLF1;BZLF1 244;168;11 249;173;12 24705134 Nuclear translocation and regulation of intranuclear distribution of cytoplasmic poly(A)-binding protein are distinct processes mediated by two Epstein Barr virus proteins. The mutants Z(N182K) and Z(S186E) each caused a statistically significant decrease in new protein synthesis compared to the vector (Table 3). 2014 PloS one Result EBV N182K;S186E 14;27 19;32 BZLF1;BZLF1 12;25 13;26 24705134 Nuclear translocation and regulation of intranuclear distribution of cytoplasmic poly(A)-binding protein are distinct processes mediated by two Epstein Barr virus proteins. The Z(S186E) and Z(N182K) mutants also showed significant decreases in new protein synthesis. 2014 PloS one Result EBV S186E;N182K 6;19 11;24 BZLF1;BZLF1 4;17 5;18 24705134 Nuclear translocation and regulation of intranuclear distribution of cytoplasmic poly(A)-binding protein are distinct processes mediated by two Epstein Barr virus proteins. To investigate mechanisms by which activities of ZEBRA regulate translocation and intranuclear distribution of PABPC, we used three point mutants of ZEBRA, Z(N182K), Z(S186A), and Z(S186E), each defective for transcriptional activation of downstream lytic viral genes. 2014 PloS one Result EBV N182K;S186A;S186E 158;168;182 163;173;187 BZLF1;BZLF1;BZLF1;BZLF1;BZLF1 49;149;156;166;180 54;154;157;167;181 24705134 Nuclear translocation and regulation of intranuclear distribution of cytoplasmic poly(A)-binding protein are distinct processes mediated by two Epstein Barr virus proteins. To measure the effect of ZEBRA on GFP protein, and to correlate the ZEBRA-mediated translocation of PABPC with shutoff, WT ZEBRA, Z(N182K), Z(S186A), and Z(S186E) were co-transfected with GFP. 2014 PloS one Result EBV N182K;S186A;S186E 132;142;156 137;147;161 BZLF1;BZLF1;BZLF1;BZLF1;BZLF1;BZLF1 25;68;123;130;140;154 30;73;128;131;141;155 24705134 Nuclear translocation and regulation of intranuclear distribution of cytoplasmic poly(A)-binding protein are distinct processes mediated by two Epstein Barr virus proteins. Transfection of Z(N182K) and Z(S186A) into 293 cells caused nuclear translocation of PABPC. 2014 PloS one Result EBV N182K;S186A 18;31 23;36 BZLF1;BZLF1 16;29 17;30 24705134 Nuclear translocation and regulation of intranuclear distribution of cytoplasmic poly(A)-binding protein are distinct processes mediated by two Epstein Barr virus proteins. When Z(R183E) was co-transfected with BGLF5, PABPC adopted a distribution similar to ZEBRA in aggresomes and small aggregates. 2014 PloS one Result EBV R183E 7 12 BGLF5;BZLF1;BZLF1 38;85;5 43;90;6 24705134 Nuclear translocation and regulation of intranuclear distribution of cytoplasmic poly(A)-binding protein are distinct processes mediated by two Epstein Barr virus proteins. Z(N182K) and Z(S186A) reduced expression of GFP by 36%, and 29%, respectively, compared to the vector control. 2014 PloS one Result EBV N182K;S186A 2;15 7;20 BZLF1;BZLF1 0;13 1;14 24705134 Nuclear translocation and regulation of intranuclear distribution of cytoplasmic poly(A)-binding protein are distinct processes mediated by two Epstein Barr virus proteins. Z(N182K) and Z(S186E) are defective for binding the high affinity ZIIIB ZEBRA response element (ZRE). 2014 PloS one Result EBV N182K;S186E 2;15 7;20 BZLF1;BZLF1;BZLF1 72;0;13 77;1;14 24705134 Nuclear translocation and regulation of intranuclear distribution of cytoplasmic poly(A)-binding protein are distinct processes mediated by two Epstein Barr virus proteins. Z(S186A) and Z(S186E) distribute evenly and diffusely in the nucleus similarly to WT ZEBRA; Z(N182K) is diffusely yet unevenly distributed. 2014 PloS one Result EBV S186A;S186E;N182K 2;15;94 7;20;99 BZLF1;BZLF1;BZLF1;BZLF1 85;0;13;92 90;1;14;93 24705134 Nuclear translocation and regulation of intranuclear distribution of cytoplasmic poly(A)-binding protein are distinct processes mediated by two Epstein Barr virus proteins. Z(S186E), which was most impaired in host shutoff, was statistically significantly different compared to WT ZEBRA (p value<0.0057) (Table 4). 2014 PloS one Result EBV S186E 2 7 BZLF1;BZLF1 108;0 113;1 25865256 Exosomal sorting of the viral oncoprotein LMP1 is restrained by TRAF2 association at signalling endosomes. Indeed, LMP1-C78A was seemingly equally efficient in recruiting TRAF2 when compared to wtLMP1, suggesting the mutant may still activate NFkappaB. 2015 Journal of extracellular vesicles Result EBV C78A 12 17 LMP1;LMP1 8;89 12;93 25865256 Exosomal sorting of the viral oncoprotein LMP1 is restrained by TRAF2 association at signalling endosomes. Next, we determined whether LMP1-C78A still recruits TRAF2 in HEK293 cells. 2015 Journal of extracellular vesicles Result EBV C78A 32 37 LMP1 28 32 25865256 Exosomal sorting of the viral oncoprotein LMP1 is restrained by TRAF2 association at signalling endosomes. Notably, these endosomal ring-like structures are reminiscent of "swollen" endosomes observed in activated Rab5 (or Rab5-Q79L) endosomes in v-Src expressing cells. 2015 Journal of extracellular vesicles Result EBV Q79L 120 125 25865256 Exosomal sorting of the viral oncoprotein LMP1 is restrained by TRAF2 association at signalling endosomes. Somewhat surprisingly, dual NFkappaB-luciferase reporter assays revealed that LMP1-C78A activated NFkappaB at comparable levels as wtLMP1. 2015 Journal of extracellular vesicles Result EBV C78A 82 87 LMP1;LMP1 78;133 82;137 25865256 Exosomal sorting of the viral oncoprotein LMP1 is restrained by TRAF2 association at signalling endosomes. Surprisingly, the wtLMP1-transfected cells formed many more colonies compared to LMP1-C78A, indicating that despite its TRAF2 clustering and NFkappaB activation potency, the trafficking mutant of LMP1 has reduced transformation efficiency. 2015 Journal of extracellular vesicles Result EBV C78A 85 90 LMP1;LMP1;LMP1 20;81;196 24;85;200 25865256 Exosomal sorting of the viral oncoprotein LMP1 is restrained by TRAF2 association at signalling endosomes. The results show that LMP1-C78A is precluded from sorting into exosomes, whereas the levels of HSP70, a common exosomal marker, were not affected. 2015 Journal of extracellular vesicles Result EBV C78A 26 31 LMP1 22 26 25865256 Exosomal sorting of the viral oncoprotein LMP1 is restrained by TRAF2 association at signalling endosomes. To establish a functional role for palmitoylation in the targeting of oncoproteins to late endosomes, we generated an EBV-LMP1 mutant (LMP1-C78A) in which cysteine 78, a confirmed LMP1 palmitoylation site, is changed into an alanine. 2015 Journal of extracellular vesicles Result EBV C78A 139 144 LMP1;LMP1;LMP1 122;135;180 126;139;184 25865256 Exosomal sorting of the viral oncoprotein LMP1 is restrained by TRAF2 association at signalling endosomes. To investigate if the altered distribution of LMP1-C78A affects oncogenicity, we performed transformation assays of HEK293 cells upon transfection with wtLMP1 and LMP1-C78A. 2015 Journal of extracellular vesicles Result EBV C78A;C78A 50;167 55;172 LMP1;LMP1;LMP1 46;154;163 50;158;167 25865256 Exosomal sorting of the viral oncoprotein LMP1 is restrained by TRAF2 association at signalling endosomes. To study whether palmitoylation of LMP1 is required for sorting into exosomes, we performed Western blotting analysis on cell lysates and corresponding exosomes purified from supernatant of HEK293 cells transfected with wtLMP1 or LMP1-C78A. 2015 Journal of extracellular vesicles Result EBV C78A 234 239 LMP1;LMP1;LMP1 35;222;230 39;226;234 25865256 Exosomal sorting of the viral oncoprotein LMP1 is restrained by TRAF2 association at signalling endosomes. We transfected HEK293 cells with wtLMP1 or LMP1-C78A, and visualized both LMP1 and CD63 with fluorescent antibodies. 2015 Journal of extracellular vesicles Result EBV C78A 47 52 LMP1;LMP1;LMP1 35;43;74 39;47;78 25950714 DNA Damage Signaling Is Induced in the Absence of Epstein-Barr Virus (EBV) Lytic DNA Replication and in Response to Expression of ZEBRA. Although Z(N182E) is defective in binding ZIIIB sites, it binds to AP1 DNA sequences comparably to wild type ZEBRA (S5 Fig). 2015 PloS one Result EBV N182E 11 16 BZLF1;BZLF1 109;9 114;10 25950714 DNA Damage Signaling Is Induced in the Absence of Epstein-Barr Virus (EBV) Lytic DNA Replication and in Response to Expression of ZEBRA. As seen with wild-type ZEBRA (Fig 9A and 9B and Fig 10A:ii), the Z(S186A) (Fig 10A:iii and 10B) and Z(N182E) (Fig 10A:iv and 10B) mutants induced pATM foci in a significant proportion of 293 cells relative to the negative control (Fig 10B). 2015 PloS one Result EBV S186A;N182E 67;102 72;107 BZLF1;BZLF1;BZLF1 23;65;100 28;66;101 25950714 DNA Damage Signaling Is Induced in the Absence of Epstein-Barr Virus (EBV) Lytic DNA Replication and in Response to Expression of ZEBRA. Foci of pATM were also detected in EBV-positive Raji cells expressing the Z(R179A) (Fig 11A:ii) and Z(S186A) (Fig 11A:iii) mutants. 2015 PloS one Result EBV R179A;S186A 76;102 81;107 BZLF1;BZLF1 74;100 75;101 25950714 DNA Damage Signaling Is Induced in the Absence of Epstein-Barr Virus (EBV) Lytic DNA Replication and in Response to Expression of ZEBRA. However, the proportion of pATM positive cells in response to expression of DNA binding defective mutants Z(S186E) (Fig 10A: v and 10B) and Z(R183E) was not significantly different from negative control cells (Fig 10A: i and 10B). 2015 PloS one Result EBV S186E;R183E 108;142 113;147 BZLF1;BZLF1 106;140 107;141 25950714 DNA Damage Signaling Is Induced in the Absence of Epstein-Barr Virus (EBV) Lytic DNA Replication and in Response to Expression of ZEBRA. Of these defective mutants, only Z(S186A) binds to the ZIIIB ZEBRA binding DNA site (Table 1). 2015 PloS one Result EBV S186A 35 40 BZLF1;BZLF1 61;33 66;34 25950714 DNA Damage Signaling Is Induced in the Absence of Epstein-Barr Virus (EBV) Lytic DNA Replication and in Response to Expression of ZEBRA. We compared the relative ability of Z(R179A), Z(S186A), Z(S186E), Z(N182E), and Z(R183E) mutants to activate pATM foci relative to wild type ZEBRA. 2015 PloS one Result EBV R179A;S186A;S186E;N182E;R183E 38;48;58;68;82 43;53;63;73;87 BZLF1;BZLF1;BZLF1;BZLF1;BZLF1;BZLF1 141;36;46;56;66;80 146;37;47;57;67;81 25950714 DNA Damage Signaling Is Induced in the Absence of Epstein-Barr Virus (EBV) Lytic DNA Replication and in Response to Expression of ZEBRA. We have previously studied DNA binding and lytic cycle activation properties of ZEBRA mutants, including Z(R179A), Z(S186A), Z(S186E), Z(N182E), and Z(R183E) (Table 1 and). 2015 PloS one Result EBV R179A;S186A;S186E;N182E;R183E 107;117;127;137;151 112;122;132;142;156 BZLF1;BZLF1;BZLF1;BZLF1;BZLF1;BZLF1 80;105;115;125;135;149 85;106;116;126;136;150 25950714 DNA Damage Signaling Is Induced in the Absence of Epstein-Barr Virus (EBV) Lytic DNA Replication and in Response to Expression of ZEBRA. Z(R179A) activates expression of Rta but not EA-D or late lytic proteins when expressed in 2089 EBV-positive cells (Table 1). 2015 PloS one Result EBV R179A 2 7 BMRF1;BRLF1;BZLF1 45;33;0 49;36;1 25950714 DNA Damage Signaling Is Induced in the Absence of Epstein-Barr Virus (EBV) Lytic DNA Replication and in Response to Expression of ZEBRA. Z(S186A), Z(S186E), Z(N182E), and Z(R183E) mutants are defective in EBV lytic cycle activation. 2015 PloS one Result EBV S186A;S186E;N182E;R183E 2;12;22;36 7;17;27;41 BZLF1;BZLF1;BZLF1;BZLF1 0;10;20;34 1;11;21;35 26337172 Sequence analysis of Epstein-Barr virus (EBV) early genes BARF1 and BHRF1 in NK/T cell lymphoma from Northern China. alpha4 helix had the dominant mutation L88V in 41 samples (77.4 %). 2015 Virology journal Result EBV L88V 39 43 26337172 Sequence analysis of Epstein-Barr virus (EBV) early genes BARF1 and BHRF1 in NK/T cell lymphoma from Northern China. At the transforming domain, only 1 more amino acid mutation was obtained in 1 isolate except for the V29A change. 2015 Virology journal Result EBV V29A 101 105 26337172 Sequence analysis of Epstein-Barr virus (EBV) early genes BARF1 and BHRF1 in NK/T cell lymphoma from Northern China. Considering the conservation of amino acid mutation and the mutual exclusion of mutations at the site of AA 79 and AA 88, the NK/T cell lymphoma cases were divided into 3 subtypes: 79V88V, 79L88L and 79V88L, the former two subtype carrying L88V, V79L mutations respectively, while the latter one without amino acid substitutions at these two residues. 2015 Virology journal Result EBV L88V;V79L 240;246 244;250 NK/T-cell lymphoma 126 144 26337172 Sequence analysis of Epstein-Barr virus (EBV) early genes BARF1 and BHRF1 in NK/T cell lymphoma from Northern China. The hottest V29A was detected at position 6 of epitope p23-31 or position 7 of p22-30 in 5 of 47 NK/T cell lymphoma isolates. 2015 Virology journal Result EBV V29A 12 16 NK/T-cell lymphoma 97 115 26337172 Sequence analysis of Epstein-Barr virus (EBV) early genes BARF1 and BHRF1 in NK/T cell lymphoma from Northern China. The most frequent amino acid mutation was AA 29 Val Ala and 5 cases with this mutation were grouped into subtype V29A. 2015 Virology journal Result EBV V29A 115 119 26337172 Sequence analysis of Epstein-Barr virus (EBV) early genes BARF1 and BHRF1 in NK/T cell lymphoma from Northern China. This homology domain was also shown to be conserved in all NK/T cell lymphoma samples except F151L in 1 sample. 2015 Virology journal Result EBV F151L 93 98 NK/T-cell lymphoma 59 77 26675171 A single nucleotide polymorphism in the Epstein-Barr virus genome is strongly associated with a high risk of nasopharyngeal carcinoma. 2c), suggesting that the SNP G155391A is functionally regulating the protein stability of RPMS1. 2015 Chinese journal of cancer Result EBV G155391A 29 37 RPMS1 90 95 26675171 A single nucleotide polymorphism in the Epstein-Barr virus genome is strongly associated with a high risk of nasopharyngeal carcinoma. As further confirmation, logistic regression analysis for SNP G155391A was conducted in another sample group from Shandong Province in North China, which is a NPC non-endemic region, involving 58 NPC patients and 612 healthy controls (Data_SD). 2015 Chinese journal of cancer Result EBV G155391A 62 70 Nasopharyngeal carcinoma;Nasopharyngeal carcinoma 196;159 199;162 26675171 A single nucleotide polymorphism in the Epstein-Barr virus genome is strongly associated with a high risk of nasopharyngeal carcinoma. Association of RPMS1 SNP G155391A and incidences of NPC and other malignancies. 2015 Chinese journal of cancer Result EBV G155391A 25 33 RPMS1 15 20 Nasopharyngeal carcinoma 52 55 26675171 A single nucleotide polymorphism in the Epstein-Barr virus genome is strongly associated with a high risk of nasopharyngeal carcinoma. High frequencies of SNP G155391A were detected among the controls from Guangdong (48.4%), whereas the frequencies were significantly lower in North China (1.2%-8.0%) and Europe (0) (P < 0.001; Table 5). 2015 Chinese journal of cancer Result EBV G155391A 24 32 26675171 A single nucleotide polymorphism in the Epstein-Barr virus genome is strongly associated with a high risk of nasopharyngeal carcinoma. Interestingly, no evidence of association was observed between the RPMS1 SNP G155391A and the risks of tested cancers except for NPC (P > 0.05; Table 6), suggesting that the association with the high-risk EBV variant might be specific to NPC. 2015 Chinese journal of cancer Result EBV G155391A 77 85 RPMS1 67 72 Nasopharyngeal carcinoma;Nasopharyngeal carcinoma 129;238 132;241 26675171 A single nucleotide polymorphism in the Epstein-Barr virus genome is strongly associated with a high risk of nasopharyngeal carcinoma. Logistic regression analysis showed that SNP G155391A was significantly associated with a high NPC risk in both sample groups (Data_GD2: P < 0.001, OR = 5.20, 95% CI 3.18-8.50; Data_GD3: P < 0.001, OR = 5.27, 95% CI 4.06-6.85; Table 4), indicating that the strong association was replicated in the two independent sample groups. 2015 Chinese journal of cancer Result EBV G155391A 45 53 Nasopharyngeal carcinoma 95 98 26675171 A single nucleotide polymorphism in the Epstein-Barr virus genome is strongly associated with a high risk of nasopharyngeal carcinoma. Logistic regression analysis with adjustment for age and gender revealed a strong association of the SNP at Loc155391 (named as G155391A) with a high risk of NPC (P < 0.001, OR = 4.47, 95% CI 2.71-7.37; Table 4). 2015 Chinese journal of cancer Result EBV G155391A 128 136 Nasopharyngeal carcinoma 158 161 26675171 A single nucleotide polymorphism in the Epstein-Barr virus genome is strongly associated with a high risk of nasopharyngeal carcinoma. Meta-analysis of all the four samples with a total of 1109 NPC patients and 2052 healthy controls showed that SNP G155391A was associated with a high risk of NPC among all tested regions (P < 0.001, OR = 5.27, 95% CI 4.31-6.44), and there was no evidence of heterogeneity among the included cohorts (P = 0.71; Table 4). 2015 Chinese journal of cancer Result EBV G155391A 114 122 Nasopharyngeal carcinoma;Nasopharyngeal carcinoma 59;158 62;161 26675171 A single nucleotide polymorphism in the Epstein-Barr virus genome is strongly associated with a high risk of nasopharyngeal carcinoma. Moreover, as Burkitt's lymphoma, Hodgkin's lymphoma, NK/T-cell lymphoma, and some gastric cancers are well known as EBV-related malignancies, we compared the distributions of the RPMS1 SNP G155391A between other cancer samples and healthy controls. 2015 Chinese journal of cancer Result EBV G155391A 189 197 RPMS1 179 184 Burkitt lymphoma;Hodgkin lymphoma;NK/T-cell lymphoma;Gastric carcinoma;EBV-related malignancy 13;33;53;82;116 31;51;71;97;140 26675171 A single nucleotide polymorphism in the Epstein-Barr virus genome is strongly associated with a high risk of nasopharyngeal carcinoma. The frequencies of SNP G155391A were counted and compared among samples from Guangdong in South China, which is an NPC endemic region, as well as in North China and Europe, where NPC incidence is relatively low. 2015 Chinese journal of cancer Result EBV G155391A 23 31 Nasopharyngeal carcinoma;Nasopharyngeal carcinoma 179;115 182;118 26675171 A single nucleotide polymorphism in the Epstein-Barr virus genome is strongly associated with a high risk of nasopharyngeal carcinoma. The increasing trend in the frequency of SNP G155391A in samples from regions with low to high NPC incidence was consistently observed in NPC patients, using either TW or TB samples (both P < 0.001; Table 5). 2015 Chinese journal of cancer Result EBV G155391A 45 53 Nasopharyngeal carcinoma;Nasopharyngeal carcinoma 95;138 98;141 26675171 A single nucleotide polymorphism in the Epstein-Barr virus genome is strongly associated with a high risk of nasopharyngeal carcinoma. The result revealed a consistently strong association between SNP G155391A and a high NPC risk (P < 0.001, OR = 7.52, 95% CI 3.69-15.32; Table 4), indicating that the association was further replicated. 2015 Chinese journal of cancer Result EBV G155391A 66 74 Nasopharyngeal carcinoma 86 89 26675171 A single nucleotide polymorphism in the Epstein-Barr virus genome is strongly associated with a high risk of nasopharyngeal carcinoma. The SNP was recognized as Loc155391 (G>A) based on its coordinates mapping to the wild-type EBV genome. 2015 Chinese journal of cancer Result EBV L155391A;G155391A 29;29 41;41 26675171 A single nucleotide polymorphism in the Epstein-Barr virus genome is strongly associated with a high risk of nasopharyngeal carcinoma. These results indicated that the frequency of SNP G155391A was associated with the NPC incidence and was significantly increased in the tumor tissues. 2015 Chinese journal of cancer Result EBV G155391A 50 58 Nasopharyngeal carcinoma 83 86 26675171 A single nucleotide polymorphism in the Epstein-Barr virus genome is strongly associated with a high risk of nasopharyngeal carcinoma. Thus, we suspected that the variation of G155391A from guanine (G) to adenine (A), leading to the amino acid change from Asp (D) to Asn (N), might be related to RPMS1 transcription or expression. 2015 Chinese journal of cancer Result EBV G155391A 41 49 RPMS1 161 166 26675171 A single nucleotide polymorphism in the Epstein-Barr virus genome is strongly associated with a high risk of nasopharyngeal carcinoma. We found one SNP in RPMS1 (Loc155391 G>A) with a significant difference between the cases and controls, and all the subsequent experiments on larger sample sizes were then focused on this genomic variation. 2015 Chinese journal of cancer Result EBV L155391A;G155391A 29;29 40;40 RPMS1 20 25 27009860 ERK2 phosphorylation of EBNA1 serine 383 residue is important for EBNA1-dependent transactivation. 526-528 526LAI528 526PAS528), but not of the near cyclin-binding motif (T582F). 2016 Oncotarget Result EBV T582F 74 79 27009860 ERK2 phosphorylation of EBNA1 serine 383 residue is important for EBNA1-dependent transactivation. In another assay based on EBNA1-dependent transactivation of an OriP-harboring reporter, EBNA1 S383A, I528S, or DM showed much lower activity (< ~50%, 39%, and 10%, respectively) (Figure 3A). 2016 Oncotarget Result EBV S383A;I528S 95;102 100;107 EBNA1;EBNA1 26;89 31;94 27009860 ERK2 phosphorylation of EBNA1 serine 383 residue is important for EBNA1-dependent transactivation. No substantial differences in EBNA1 subcellular localization or expression could be found between WT and S383A EBNA1.expressing cells upon U0126 treatment (Supplementary Figure S2A). 2016 Oncotarget Result EBV S383A 105 110 EBNA1;EBNA1 30;111 35;116 27009860 ERK2 phosphorylation of EBNA1 serine 383 residue is important for EBNA1-dependent transactivation. Phosphorylation was entirely abrogated in the case of a point mutation at a putative phosphorylation site (denoted S383A), suggesting that ERK2 phosphorylated EBNA1 at serine 383 (S383). 2016 Oncotarget Result EBV S383A 115 120 EBNA1 159 164 27009860 ERK2 phosphorylation of EBNA1 serine 383 residue is important for EBNA1-dependent transactivation. Point mutation at I528S also impaired phosphorylation, albeit less effectively. 2016 Oncotarget Result EBV I528S 18 23 27009860 ERK2 phosphorylation of EBNA1 serine 383 residue is important for EBNA1-dependent transactivation. Similarly, live cell confocal microscopy showed that the subcellular localizations of stably expressed EGFP-EBNA1 S383 or S383A were almost identical in BJAB cells. 2016 Oncotarget Result EBV S383A 122 127 EBNA1 108 113 27009860 ERK2 phosphorylation of EBNA1 serine 383 residue is important for EBNA1-dependent transactivation. This additional inhibitory effect was significantly diminished in S383A, further confirming that S383 was the primary target for U0126 and H20 (Figure 3B). 2016 Oncotarget Result EBV S383A 66 71 27009860 ERK2 phosphorylation of EBNA1 serine 383 residue is important for EBNA1-dependent transactivation. This indicates that the S383A mutation did not affect EBNA1 subcellular localization or shuttling between nucleus and cytoplasm (Supplementary Figure S2B). 2016 Oncotarget Result EBV S383A 24 29 EBNA1 54 59 27009860 ERK2 phosphorylation of EBNA1 serine 383 residue is important for EBNA1-dependent transactivation. To explore the effect of mutation or U0126 treatment on EBNA1 sub cellular localization, BJAB cells stably expressing FLAG-EBNA1 S383 (FE1 S383) or S383A (FE1 S383A) were treated with dimethyl sulfoxide (DMSO) (-) or U0126 (10 muM) for 4 days. 2016 Oncotarget Result EBV S383A;S383A 148;159 153;164 EBNA1;EBNA1 56;123 61;128 27009860 ERK2 phosphorylation of EBNA1 serine 383 residue is important for EBNA1-dependent transactivation. Treatment with U0126 or S383A mutation have no significant effect on EBNA1 nuclear or cytoplasmic localization. 2016 Oncotarget Result EBV S383A 24 29 EBNA1 69 74 27009860 ERK2 phosphorylation of EBNA1 serine 383 residue is important for EBNA1-dependent transactivation. While transcriptional activity of WT EBNA1 was >140 fold, S383A and S383D had only 32 fold (22% of WT) and 92 fold activity (~66% of WT), respectively (Figure 3A). 2016 Oncotarget Result EBV S383A;S383D 58;68 63;73 EBNA1 37 42 27009860 ERK2 phosphorylation of EBNA1 serine 383 residue is important for EBNA1-dependent transactivation. Wild-type (WT) EBNA1 (S383), phosphorylation-deficient alanine (S383A), and phosphomimetic peptide (S383D) substitutions were tested for transactivation function in a full-length FE1 background in the presence or absence of U0126, and H20, or ERK2 siRNA. 2016 Oncotarget Result EBV S383A;S383D 64;100 69;105 EBNA1 15 20 27009860 ERK2 phosphorylation of EBNA1 serine 383 residue is important for EBNA1-dependent transactivation. WT- and S383D-dependent transactivation functions were repressed by H20 and U0126. 2016 Oncotarget Result EBV S383D 8 13 29221111 Nasopharyngeal carcinoma risk prediction via salivary detection of host and Epstein-Barr virus genetic variants. Based on genotyping for RPMS1 using nested PCR and Sanger sequencing methods in study population 1, we found that the frequencies of G155391A were significantly higher in the 50 matched samples from NPC patients (84% in tumor biopsy samples and 82% in tumor washing samples) than that in 54 healthy throat washing samples (39%) (Table 1). 2017 Oncotarget Result EBV G155391A 133 141 RPMS1 24 29 Nasopharyngeal carcinoma 199 202 29221111 Nasopharyngeal carcinoma risk prediction via salivary detection of host and Epstein-Barr virus genetic variants. G155391A was also significantly associated with NPC in study population 3 (OR = 5.74, 95% CI = 4.42-7.46, P = 2.56 x 10-39) (Table 4). 2017 Oncotarget Result EBV G155391A 0 8 Nasopharyngeal carcinoma 48 51 29221111 Nasopharyngeal carcinoma risk prediction via salivary detection of host and Epstein-Barr virus genetic variants. These results confirmed the strong association of G155391A in RPMS1 of EBV with NPC risk in patients from Guangdong Province. 2017 Oncotarget Result EBV G155391A 50 58 RPMS1 62 67 Nasopharyngeal carcinoma 80 83 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. 5hmC abrogates Zta(C189A) and Zta(C189V) binding (Fig S5D-E) with all 8-mers being weakly bound relative to wild-type Zta (Fig 3C-D,S3F). 2018 Biochemical and biophysical research communications Result EBV C189A;C189V 19;34 24;39 BZLF1;BZLF1;BZLF1 15;30;118 18;33;121 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. 8-mers containing the canonical TRE (TGAC/GTCA) are more specifically bound (higher Z-scores) by Zta(C189S). 2018 Biochemical and biophysical research communications Result EBV C189S 101 106 BZLF1 97 100 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. Additional 8-mers are more strongly bound by Zta(C189S) and Zta(C189T) mutants when both cytosines are methylated at C2G3 (Fig S8). 2018 Biochemical and biophysical research communications Result EBV C189S;C189T 49;64 54;69 BZLF1;BZLF1 45;60 48;63 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. Again, Zta(C189T) has similar binding properties to Zta(C189S) (Fig 3B, S3E). 2018 Biochemical and biophysical research communications Result EBV C189T;C189S 11;56 16;61 BZLF1;BZLF1 7;52 10;55 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. As summarized in the introduction, the serine in Zta(C189S) of each Zta monomer interacts via hydrogen bonds (bold red lines, Fig S9A) with the phosphate backbone upstream of the thymines at each end of the meZRE2 (T-4 and T-4'), as well as additional van der Waals interactions with T-4 and the methylated cytosine of the opposite strand of meZRE2 (M-3') (bold black lines, Fig S9A and). 2018 Biochemical and biophysical research communications Result EBV C189S 53 58 BZLF1;BZLF1 49;68 52;71 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. Features containing the C/EBP half-site GC2AA are better bound by Zta, while features containing the TRE motif are preferentially bound by the Zta(C189S), and Zta(C189T) mutants (Table S4). 2018 Biochemical and biophysical research communications Result EBV C189S;C189T 147;163 152;168 BZLF1;BZLF1;BZLF1 66;143;159 69;146;162 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. Fig 1E is a scatterplot of Z-scores for Zta (x-axis) and Zta(C189S) (y-axis) binding all 32,896 8-mers of DNA(C C), where complements are combined. 2018 Biochemical and biophysical research communications Result EBV C189S 61 66 BZLF1;BZLF1 40;57 43;60 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. Fig 3A presents a comparison of Z-scores for binding DNA(5hmC C) 8-mers for Zta (x-axis) and Zta(C189S) (y-axis). 2018 Biochemical and biophysical research communications Result EBV C189S 97 102 BZLF1;BZLF1 76;93 79;96 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. For example, Zta(C189S) has a Z-score of 52 for binding A3 and a Z-score of 211 for C3 (Table 1B). 2018 Biochemical and biophysical research communications Result EBV C189S 17 22 BZLF1 13 16 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. For Zta and Zta(C189S), many well-bound DNA(5mC C) 8-mers contain the C/EBP half-site GM2AA (Fig 2A,S4) as observed previously for Zta and CREB1. 2018 Biochemical and biophysical research communications Result EBV C189S 16 21 BZLF1;BZLF1;BZLF1 4;12;131 7;15;134 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. Greater variability is observed in comparing Zta and Zta(C189S) than their respective duplicates (R=0.85 vs. 2018 Biochemical and biophysical research communications Result EBV C189S 57 62 BZLF1;BZLF1 45;53 48;56 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. Here, DNA binding specificity correlates with the polarity gradient in the mutant side chains: a pair of polar mutants, Zta(C189S) and Zta(C189T), have a similar DNA binding profile, which is distinct from the one elicited by the two hydrophobic mutants, Zta(C189A) and Zta(C189V). 2018 Biochemical and biophysical research communications Result EBV C189S;C189T;C189A;C189V 124;139;259;274 129;144;264;279 BZLF1;BZLF1;BZLF1;BZLF1 120;135;255;270 123;138;258;273 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. Here, when A3 is replaced with C3, the Z-score is not greatly affected for Zta (decreases from 162 to 145) (Table 1A), whereas binding increases for Zta(C189S) (Table 1B) and all other mutants (Table S7). 2018 Biochemical and biophysical research communications Result EBV C189S 153 158 BZLF1;BZLF1 75;149 78;152 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. In addition, several non-GM2AA containing 8-mers are more strongly bound by Zta(C189S), including those that contain the subsequence TGTGM2A (Fig 2A, labelled). 2018 Biochemical and biophysical research communications Result EBV C189S 80 85 BZLF1 76 79 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. In contrast, Zta(C189A) and Zta(C189V) bind most DNA(5mCG) 8-mers worse than Zta (Fig 4C-D; Fig S6D-E). 2018 Biochemical and biophysical research communications Result EBV C189A;C189V 17;32 22;37 BZLF1;BZLF1;BZLF1 13;28;77 16;31;80 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. Like Zta(C189S), 8-mers containing the TRE motif are preferentially bound relative to Zta (Fig 1F). 2018 Biochemical and biophysical research communications Result EBV C189S 9 14 BZLF1;BZLF1 5;86 8;89 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. Most DNA(5mCG) 8-mers, however, are not as strongly bound by Zta(C189S) and Zta(C189T) compared to Zta, including 8-mers containing the meZRE3 sequence (Table S5B), consistent with previously reported results. 2018 Biochemical and biophysical research communications Result EBV C189S;C189T 65;80 70;85 BZLF1;BZLF1;BZLF1 61;76;99 64;79;102 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. Table 2 presents Z-scores for Zta and Zta(C189S) binding a non-cytosine containing ZRE2 motif variant TGAGT2GA. 2018 Biochemical and biophysical research communications Result EBV C189S 42 47 BZLF1;BZLF1 30;38 33;41 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. To examine the structural basis of the differences in DNA binding between Zta and C189 mutants, we examined nucleotide-residue contact maps for Zta(C189S) (PDB: 5szx) (Fig S9A) binding the canonical meZRE2 motif (TGAGM2GA, complement: TM-3'GCTCA) and a structure where serine is changed to cysteine (Fig S9B). 2018 Biochemical and biophysical research communications Result EBV C189S 148 153 BZLF1;BZLF1 74;144 77;147 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. We next examined Zta(C189T) binding to 8-mers containing DNA(C C). 2018 Biochemical and biophysical research communications Result EBV C189T 21 26 BZLF1 17 20 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. While most GM2AA-containing 8-mers are better bound by Zta compared to Zta(C189S), several 8-mers are strongly bound by both proteins (e.g. 2018 Biochemical and biophysical research communications Result EBV C189S 75 80 BZLF1;BZLF1 55;71 58;74 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. Zta, Zta(C189S), and Zta(C189T) bind many features containing DNA(5mC C), and median and average fluorescent intensity for all features increases relative to DNA(C C) (Table S2). 2018 Biochemical and biophysical research communications Result EBV C189S;C189T 9;25 14;30 BZLF1;BZLF1;BZLF1 0;5;21 3;8;24 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. Zta(C189A) and Zta(C189V) bind most 8-mers weakly as observed for binding DNA(C C) with the exception of the 8-mers ATGAGM2AA and TGAGM2AAT (Fig 2C-D, S3D). 2018 Biochemical and biophysical research communications Result EBV C189A;C189V 4;19 9;24 BZLF1;BZLF1 0;15 3;18 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. Zta(C189A) and Zta(C189V) bind the TRE sequence, but not as strongly as Zta (Fig 1G-H). 2018 Biochemical and biophysical research communications Result EBV C189A;C189V 4;19 9;24 BZLF1;BZLF1;BZLF1 0;15;72 3;18;75 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. Zta(C189S) and Zta(C189T) mutants bind several DNA(5mCG) 8-mers, including those that contain the meZRE2 and the meZRE2-like sequence TGTGMGA (Fig 4A-B,S6B-C; Table S5A). 2018 Biochemical and biophysical research communications Result EBV C189S;C189T 4;19 9;24 BZLF1;BZLF1 0;15 3;18 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. Zta(C189S) and Zta(C189T), and Zta(C189A) and Zta(C189V) bind DNA(C C) 8-mers similarly, as may be expected as these pairs of amino acids have similar physico-chemical properties (Fig S3A-B). 2018 Biochemical and biophysical research communications Result EBV C189S;C189T;C189A;C189V 4;19;35;50 9;24;40;55 BZLF1;BZLF1;BZLF1;BZLF1 0;15;31;46 3;18;34;49 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. Zta(C189S) binds several 8-mers containing the hydroxymethylated C/EBP half-site GH2AA, similar to Zta (e.g. 2018 Biochemical and biophysical research communications Result EBV C189S 4 9 BZLF1;BZLF1 0;99 3;102 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. Zta(C189T) binds similar DNA(5mC C) 8-mers as Zta(C189S) (Fig 2B and Fig S3C). 2018 Biochemical and biophysical research communications Result EBV C189T;C189S 4;50 9;55 BZLF1;BZLF1 0;46 3;49 31481499 Integrated Pan-Cancer Map of EBV-Associated Neoplasms Reveals Functional Host-Virus Interactions. Importantly, nearly all EBV+ NPC and DLBCL samples, and one-third of NKTCL samples, had one or two frequent nonsense variations in the LMP1 protein, Q322X and G342X. 2019 Cancer research Result EBV Q322X;G342X 149;159 154;164 LMP1 135 139 Nasopharyngeal carcinoma;Diffuse large B cell lymphomas 29;37 32;42 33633271 The influence of human genetic variation on Epstein-Barr virus sequence diversity. 2B) and the EBV amino acid BRLF1:p.Lys316Glu. 2021 Scientific reports Result EBV K316E 33 44 BRLF1 27 32 33633271 The influence of human genetic variation on Epstein-Barr virus sequence diversity. BRLF1:p.Lys316Glu and BRLF1:p.Glu377Ala are in moderate LD (r2 = 0.55) in our dataset. 2021 Scientific reports Result EBV K316E;E377A 6;28 17;39 BRLF1;BRLF1 0;22 5;27 33633271 The influence of human genetic variation on Epstein-Barr virus sequence diversity. BRLF1:p.Lys316Glu has not been described previously, but variation at the nearby residue 377 (BRLF1:p.Glu377Ala) has been shown to be prevalent in cases of nasopharyngeal and gastric carcinomas in Chinese samples. 2021 Scientific reports Result EBV K316E;E377A 6;100 17;111 BRLF1;BRLF1 0;94 5;99 Nasopharyngeal carcinoma;Gastric carcinoma 156;175 170;193 33633271 The influence of human genetic variation on Epstein-Barr virus sequence diversity. Finally, 7 SNPs mapping to a non-coding region of chromosome 7 were found to be associated with the EBV amino acid variant BRLF1:p.Lys316Glu. 2021 Scientific reports Result EBV K316E 129 140 BRLF1 123 128 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. Among the 13 residues at the interface G462A and G463A increase the binding affinity while the remaining 11 residues decrease the binding affinity at different folds. 2021 Frontiers in molecular biosciences Result EBV G462A;G463A 39;49 44;54 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. As given in Figure 4, a significant drop can be observed in the mutant complexes, particularly in the K514A, R521A and R522A complexes. 2021 Frontiers in molecular biosciences Result EBV K514A;R521A;R522A 102;109;119 107;114;124 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. As tabulated in Table 1, it can be seen that R469A, K514A, Y518A, R521A and R522A significantly affected the binding of DNA as compared to others. 2021 Frontiers in molecular biosciences Result EBV R469A;K514A;Y518A;R521A;R522A 45;52;59;66;76 50;57;64;71;81 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. For the K514A complex, the total binding energy was reported to be -104.97 +- 0.175 kcal/mol while the total binding energy for Y518A was -102.17 +- 0.190 kcal/mol. 2021 Frontiers in molecular biosciences Result EBV K514A;Y518A 8;128 13;133 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. For the Y518A the predicted DeltaG was -3.406 kcal/mol; however, the dAffinity was reported to be -1,020.32 kcal/mol. 2021 Frontiers in molecular biosciences Result EBV Y518A 8 13 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. Furthermore, the predicted DeltaG for R521A was -5.866 kcal/mol, while for R522A, it was -6.008 kcal/mol. 2021 Frontiers in molecular biosciences Result EBV R521A;R522A 38;75 43;80 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. Furthermore, the two essential residues R521A and R522A which significantly contributed to the total binding energy reported in substantial hydrogen bonds reduction between EBNA1 and DNA. 2021 Frontiers in molecular biosciences Result EBV R521A;R522A 40;50 45;55 EBNA1 173 178 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. Hence, these results also show that R469A, K514A, Y518A, R521A and R522A are required for DNA recognition and are the key hotspots for drug discovery. 2021 Frontiers in molecular biosciences Result EBV R469A;K514A;Y518A;R521A;R522A 36;43;50;57;67 41;48;55;62;72 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. However, in the R469A, this total binding energy was calculated to be -110.75 +- 0.230 kcal/mol. 2021 Frontiers in molecular biosciences Result EBV R469A 16 21 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. In case of K514A only one hydrogen bond while in case of Y518A, two important hydrogen bonds are lost. 2021 Frontiers in molecular biosciences Result EBV K514A;Y518A 11;57 16;62 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. In R522A five bonds formed by R521 and R522 are lost. 2021 Frontiers in molecular biosciences Result EBV R522A 3 8 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. In the case of R469A, the same pattern was observed. 2021 Frontiers in molecular biosciences Result EBV R469A 15 20 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. In the case of R521A and R522A, the structural compactness is disrupted significantly. 2021 Frontiers in molecular biosciences Result EBV R521A;R522A 15;25 20;30 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. In the case of R521A only 10 hydrogen bonds were reported, while only nine bonds were reported between R522A and DNA. 2021 Frontiers in molecular biosciences Result EBV R521A;R522A 15;103 20;108 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. In the case of the R469A mutation, the complex experiences significant divergence from the initial structure. 2021 Frontiers in molecular biosciences Result EBV R469A 19 24 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. In the case of the R469A, the predicted DeltaG was reported to -5.784 kcal/mol, while the dAffinity was also predicted to be reduced (-1,009.21 kcal/mol). 2021 Frontiers in molecular biosciences Result EBV R469A 19 24 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. In the case of wild type peptide complex, the first three eigenvectors contributed 35% variance to the total observed motion, while in R49A, 45%, K514 43%, Y518A 39%, R521A 54% while R522A accounted for 48% variance in motion. 2021 Frontiers in molecular biosciences Result EBV R49A;Y518A;R521A;R522A 135;156;167;183 139;161;172;188 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. In the case of Y518A, the structural compactness also remained haphazard. 2021 Frontiers in molecular biosciences Result EBV Y518A 15 20 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. Intriguingly the dAffinity for R521A and R522A was comparable. 2021 Frontiers in molecular biosciences Result EBV R521A;R522A 31;41 36;46 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. Moreover, with 12 hydrogen bonds between EBNA1 (Y518A) and DNA complex R469, R521 and R522 lost their multiple interactions which were reported to be sustained in wild type complex. 2021 Frontiers in molecular biosciences Result EBV Y518A 48 53 EBNA1 41 46 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. On the other hand, the estimated binding energy for R522A was -100.04 +- 0.215 kcal/mol. 2021 Frontiers in molecular biosciences Result EBV R522A 52 57 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. On the other hand, the K514A the Rg remained higher during the simulation time period. 2021 Frontiers in molecular biosciences Result EBV K514A 23 28 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. On the other hand, the R469A lost multiple interactions during the simulation, particularly those formed with R469 residue, consequently remaining 13 hydrogen bonds between EBNA1 and DNA. 2021 Frontiers in molecular biosciences Result EBV R469A 23 28 EBNA1 173 178 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. On the other hand, the Y518A behaviour was also comparable with the K514A. 2021 Frontiers in molecular biosciences Result EBV Y518A;K514A 23;68 28;73 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. Overall, these results show that the mutations induced significant energy drop out but the R521A and R522A reduced the binding energy by many folds. 2021 Frontiers in molecular biosciences Result EBV R521A;R522A 91;101 96;106 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. Significant drop out was observed in the total binding energy of the R521A mutant complex. 2021 Frontiers in molecular biosciences Result EBV R521A 69 74 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. Similarly, only 11 hydrogen bonds were observed in K514A complex. 2021 Frontiers in molecular biosciences Result EBV K514A 51 56 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. The average number of hydrogen bonds in the wild type was reported to be 98, while in the mutant complexes (R469A), the H-bonds were reported to be 94, (K514A) H-bonds were observed to be 90, Y518A reported 94, while the significant drop was observed in R521A (86) and R522A the total H-bonds were 88. 2021 Frontiers in molecular biosciences Result EBV R469A;K514A;Y518A;R521A;R522A 108;153;192;254;269 113;158;197;259;274 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. The average RMSD for R469A was reported to be 3.5 A. 2021 Frontiers in molecular biosciences Result EBV R469A 21 26 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. The average RMSD remained higher for R521A (5.5 A), while the average RMSD for R522A remained lower but converged significantly. 2021 Frontiers in molecular biosciences Result EBV R521A;R522A 37;79 42;84 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. The K514A mutant, which is considered as an important residue for the DNA binding, caused significant perturbation upon the substitution. 2021 Frontiers in molecular biosciences Result EBV K514A 4 9 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. The predicted dAffinity for R521A and R522A was reported to be -1,009.60 kcal/mol and -1,009.37 kcal/mol, respectively. 2021 Frontiers in molecular biosciences Result EBV R521A;R522A 28;38 33;43 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. The predicted DeltaG for K514A was reported to be -3.638 kcal/mol, while the dAffinity was reported to be -1,021.32 kcal/mol, respectively. 2021 Frontiers in molecular biosciences Result EBV K514A 25 30 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. The residues 460-480, particularly in Y518A and R522A possess more flexible behaviour than the others, which is explained in Figure 8 that it deviated more than the mean point and the mutations cause an allosteric effect on the flexibility. 2021 Frontiers in molecular biosciences Result EBV Y518A;R522A 38;48 43;53 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. The results of R469A and wild type was comparable. 2021 Frontiers in molecular biosciences Result EBV R469A 15 20 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. The TBE was for R517A was reported to be -97.93 +- 0.226 kcal/mol. 2021 Frontiers in molecular biosciences Result EBV R517A 16 21 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. The total binding energy results of K514A and Y518A mutant complexes are comparable. 2021 Frontiers in molecular biosciences Result EBV K514A;Y518A 36;46 41;51 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. The wild type, K514A, Y518A and R522A shows only one energy minima while R469A and R521A exhibit two lowest energy minima separated by a small subspace, thus explaining global conformational variations adjusted by the mutant complexes in response to mutations. 2021 Frontiers in molecular biosciences Result EBV K514A;Y518A;R522A;R469A;R521A 15;22;32;73;83 20;27;37;78;88 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. wild type, R469A, K514A, Y518A, R521A and R522A. 2021 Frontiers in molecular biosciences Result EBV R469A;K514A;Y518A;R521A;R522A 11;18;25;32;42 16;23;30;37;47 34567789 A comprehensive analysis of genetic diversity of EBV reveals potential high-risk subtypes associated with nasopharyngeal carcinoma in China. Four AA substitutions (BALF2 V317M, BNRF1 G696R, V1222I and RPMS1 D51E) were significantly associated with NPC. 2021 Virus evolution Result EBV V317M;G696R;V1222I;D51E 29;42;49;66 34;47;55;70 BNRF1;RPMS1;BALF2 36;60;23 41;65;28 Nasopharyngeal carcinoma 107 110 34567789 A comprehensive analysis of genetic diversity of EBV reveals potential high-risk subtypes associated with nasopharyngeal carcinoma in China. It is intriguing to find that many NPC-associated mutations, including BALF2 V317M and BNRF1 V1222I, were under positive selection. 2021 Virus evolution Result EBV V317M;V1222I 77;93 82;99 BNRF1;BALF2 87;71 92;76 Nasopharyngeal carcinoma 35 38 34567789 A comprehensive analysis of genetic diversity of EBV reveals potential high-risk subtypes associated with nasopharyngeal carcinoma in China. Particularly, the BNRF1 V1222I mutation, which yields the highest OR of 21.10, was further validated using our independent samples from EPI-NPC-2005 project. 2021 Virus evolution Result EBV V1222I 24 30 BNRF1 18 23 Nasopharyngeal carcinoma 140 143 26675171 A single nucleotide polymorphism in the Epstein-Barr virus genome is strongly associated with a high risk of nasopharyngeal carcinoma. We acknowledge that further studies with larger sample sizes, more ethnic groups, and more geographic regions are needed to replicate our findings and rule out the confounding effects of population and the source of EBV, as the RPMS1 SNP G155391A had much higher frequency in the Guangdong area based on TW samples. 2015 Chinese journal of cancer Conclusion EBV G155391A 238 246 RPMS1 228 233 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. In particular, the two arginine substitution R521A and R522A, significantly affected the total binding energy. 2021 Frontiers in molecular biosciences Conclusion EBV R521A;R522A 45;55 50;60 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. Our analysis revealed that R469A, K514A, Y518A, R521A and R522A are the key hotspots for drug discovery against the various tumors caused by EBV. 2021 Frontiers in molecular biosciences Conclusion EBV R469A;K514A;Y518A;R521A;R522A 27;34;41;48;58 32;39;46;53;63 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. A185V 2008 Virology Table EBV A185V 0 5 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. K181A 2008 Virology Table EBV K181A 0 5 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. K188A 2008 Virology Table EBV K188A 0 5 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. K188R 2008 Virology Table EBV K188R 0 5 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. R179A 2008 Virology Table EBV R179A 0 5 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. S186A 2008 Virology Table EBV S186A 0 5 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. S186E 2008 Virology Table EBV S186E 0 5 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. Y180E 2008 Virology Table EBV Y180E 0 5 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. D150A 2012 PloS one Table EBV D150A 0 5 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. F144I 2012 PloS one Table EBV F144I 0 5 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. I124V 2012 PloS one Table EBV I124V 0 5 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. I152L 2012 PloS one Table EBV I152L 0 5 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. L151I 2012 PloS one Table EBV L151I 0 5 24705134 Nuclear translocation and regulation of intranuclear distribution of cytoplasmic poly(A)-binding protein are distinct processes mediated by two Epstein Barr virus proteins. N182K 2014 PloS one Table EBV N182K 0 5 24705134 Nuclear translocation and regulation of intranuclear distribution of cytoplasmic poly(A)-binding protein are distinct processes mediated by two Epstein Barr virus proteins. S186A 2014 PloS one Table EBV S186A 0 5 24705134 Nuclear translocation and regulation of intranuclear distribution of cytoplasmic poly(A)-binding protein are distinct processes mediated by two Epstein Barr virus proteins. S186E 2014 PloS one Table EBV S186E 0 5 25950714 DNA Damage Signaling Is Induced in the Absence of Epstein-Barr Virus (EBV) Lytic DNA Replication and in Response to Expression of ZEBRA. N182E 2015 PloS one Table EBV N182E 0 5 25950714 DNA Damage Signaling Is Induced in the Absence of Epstein-Barr Virus (EBV) Lytic DNA Replication and in Response to Expression of ZEBRA. R179A 2015 PloS one Table EBV R179A 0 5 25950714 DNA Damage Signaling Is Induced in the Absence of Epstein-Barr Virus (EBV) Lytic DNA Replication and in Response to Expression of ZEBRA. R183E 2015 PloS one Table EBV R183E 0 5 25950714 DNA Damage Signaling Is Induced in the Absence of Epstein-Barr Virus (EBV) Lytic DNA Replication and in Response to Expression of ZEBRA. S186A 2015 PloS one Table EBV S186A 0 5 25950714 DNA Damage Signaling Is Induced in the Absence of Epstein-Barr Virus (EBV) Lytic DNA Replication and in Response to Expression of ZEBRA. S186E 2015 PloS one Table EBV S186E 0 5 26337172 Sequence analysis of Epstein-Barr virus (EBV) early genes BARF1 and BHRF1 in NK/T cell lymphoma from Northern China. V29A 2015 Virology journal Table EBV V29A 0 4 26675171 A single nucleotide polymorphism in the Epstein-Barr virus genome is strongly associated with a high risk of nasopharyngeal carcinoma. G155391A 2015 Chinese journal of cancer Table EBV G155391A 0 8 29221111 Nasopharyngeal carcinoma risk prediction via salivary detection of host and Epstein-Barr virus genetic variants. G155391A 2017 Oncotarget Table EBV G155391A 0 8 33633271 The influence of human genetic variation on Epstein-Barr virus sequence diversity. p.Lys316Glu 2021 Scientific reports Table EBV K316E 0 11 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. F465A 2021 Frontiers in molecular biosciences Table EBV F465A 0 5 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. F478A 2021 Frontiers in molecular biosciences Table EBV F478A 0 5 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. G462A 2021 Frontiers in molecular biosciences Table EBV G462A 0 5 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. G463A 2021 Frontiers in molecular biosciences Table EBV G463A 0 5 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. K477A 2021 Frontiers in molecular biosciences Table EBV K477A 0 5 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. K514A 2021 Frontiers in molecular biosciences Table EBV K514A 0 5 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. N475A 2021 Frontiers in molecular biosciences Table EBV N475A 0 5 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. R469A 2021 Frontiers in molecular biosciences Table EBV R469A 0 5 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. R491A 2021 Frontiers in molecular biosciences Table EBV R491A 0 5 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. R521A 2021 Frontiers in molecular biosciences Table EBV R521A 0 5 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. R522A 2021 Frontiers in molecular biosciences Table EBV R522A 0 5 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. W464A 2021 Frontiers in molecular biosciences Table EBV W464A 0 5 34268333 Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein-Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis. Y518A 2021 Frontiers in molecular biosciences Table EBV Y518A 0 5 34567789 A comprehensive analysis of genetic diversity of EBV reveals potential high-risk subtypes associated with nasopharyngeal carcinoma in China. D51E 2021 Virus evolution Table EBV D51E 0 4 34567789 A comprehensive analysis of genetic diversity of EBV reveals potential high-risk subtypes associated with nasopharyngeal carcinoma in China. G696R 2021 Virus evolution Table EBV G696R 0 5 34567789 A comprehensive analysis of genetic diversity of EBV reveals potential high-risk subtypes associated with nasopharyngeal carcinoma in China. V1222I 2021 Virus evolution Table EBV V1222I 0 6 34567789 A comprehensive analysis of genetic diversity of EBV reveals potential high-risk subtypes associated with nasopharyngeal carcinoma in China. V317M 2021 Virus evolution Table EBV V317M 0 5 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. (i-vi) S186A Rta-mutant ZEBRA; (vii-xii) R179A early-mutant ZEBRA; (xiii-xviii, xxv-xxx) Y180E late-mutant ZEBRA; (xix-xxiv, xxxi-xxxvi) (K188R) WT-like mutant ZEBRA. 2008 Virology Figure EBV S186A;R179A;Y180E;K188R 7;41;89;138 12;46;94;143 BZLF1;BZLF1;BZLF1;BZLF1;BRLF1 24;60;107;160;13 29;65;112;165;16 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. 2089 cells (i, ii, v, vi, ix, x, xiii, xiv, xvii, xviii) and 293 cells (iii, iv, vii, viii, xi, xii, xv, xvi, xix, xx) were transfected with expression plasmids for wild-type ZEBRA (i-iv), R179A (v-viii), Y180E (ix-xii), S186A (xiii-xvi), or K188R mutant ZEBRA (xvii-xx). 2008 Virology Figure EBV R179A;Y180E;S186A;K188R 189;205;221;242 194;210;226;247 BZLF1;BZLF1 175;255 180;260 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. 2089 cells were transfected with S186A mutant ZEBRA (i-iii), S186A plus Rta (iv-vi), K181A mutant ZEBRA (vii-ix), A185V mutant ZEBRA (x-xii), or S186E mutant ZEBRA (xiii-xv). 2008 Virology Figure EBV S186A;S186A;K181A;A185V;S186E 33;61;85;114;145 38;66;90;119;150 BZLF1;BZLF1;BZLF1;BZLF1;BRLF1 46;98;127;158;72 51;103;132;163;75 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. 2089 cells were transfected with wild-type ZEBRA (i-ix) or R179A mutant ZEBRA (x-xviii), treated with 500 muM PAA (iv-vi, xiii-xv) or 50 muM ACV (vii-ix, xvi-xviii), then fixed and double-stained for ZEBRA and EA-D. 2008 Virology Figure EBV R179A 59 64 BZLF1;BZLF1;BZLF1;BMRF1 43;72;200;210 48;77;205;214 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. D98/HR-1 cells were transfected with wild-type ZEBRA (i-vi) or R179A mutant ZEBRA (vii-xviii). 2008 Virology Figure EBV R179A 63 68 BZLF1;BZLF1 47;76 52;81 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. Effect of phosphonoacetic acid (PAA) and acyclovir (ACV) treatment on the localization of wild-type and R179A mutant ZEBRA and on the formation of replication compartments. 2008 Virology Figure EBV R179A 104 109 BZLF1 117 122 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. Nuclear localization, activation of EA-D, and replication compartment formation by wild-type and R179A mutant ZEBRA in D98/HR-1 cells. 2008 Virology Figure EBV R179A 97 102 BZLF1;BMRF1 110;36 115;40 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. Red arrow indicates a discrete foci of mutant Y180E ZEBRA in a 293 cell. 2008 Virology Figure EBV Y180E 46 51 BZLF1 52 57 19325883 Methylation-dependent binding of the epstein-barr virus BZLF1 protein to viral promoters. (A) The predicted structure and hydrogen interactions between WT Z bound to Nap ZRE2 (upper panel, stereoview) is compared to Z(S186A) bound to the AP1 site (lower panel, stereoview). 2009 PLoS pathogens Figure EBV S186A 128 133 BZLF1;BZLF1 65;126 66;127 19325883 Methylation-dependent binding of the epstein-barr virus BZLF1 protein to viral promoters. HeLa cells were transfected with methylated luciferase vectors driven by the Na or R promoters, in the presence or absence of a co-transfected wild-type Z (WTZ), or the Z(S186A) mutant altered in the DNA binding domain at residue 186. 2009 PLoS pathogens Figure EBV S186A 171 176 BZLF1;BZLF1 153;169 154;170 19325883 Methylation-dependent binding of the epstein-barr virus BZLF1 protein to viral promoters. Wild-type Z (WTZ), Z(S186A), Z(C189S) or empty vector (vector) were transfected in to 293 Z-KO cells in the presence or absence of an R expression vector and assayed by western blot for expression of Z, R, Na, EA-D or beta-actin. 2009 PLoS pathogens Figure EBV S186A;C189S 21;31 26;36 BMRF1;BZLF1;BZLF1;BZLF1;BZLF1;BZLF1 210;10;19;29;90;200 214;11;20;30;91;201 19325883 Methylation-dependent binding of the epstein-barr virus BZLF1 protein to viral promoters. Wild-type Z, but not Z(S186A), activates Na and R transcription. 2009 PLoS pathogens Figure EBV S186A 23 28 BZLF1;BZLF1 10;21 11;22 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. (A) Immunoblot of BZKO cell extracts expressing empty vector (CMV), wt ZEBRA (Z) or Z(S173A) in the absence and presence of various combinations of replication proteins. 2010 PLoS pathogens Figure EBV S173A 86 91 BZLF1;BZLF1;BZLF1 71;78;84 76;79;85 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. (A) Z(R187K) and Z(K188A) fail to activate two late proteins, FR3 and LR2. 2010 PLoS pathogens Figure EBV R187K;K188A 6;19 11;24 BZLF1;BZLF1 4;17 5;18 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. (B) The effect of replication proteins on late gene expression and viral replication activated by Z(R187K). 2010 PLoS pathogens Figure EBV R187K 100 105 BZLF1 98 99 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. A) Electrophoretic mobility shift assay (EMSA) comparing the DNA binding activity of Z(Y180E), Z(K188A), Z(K188R) and wt ZEBRA using four ZEBRA response elements. 2010 PLoS pathogens Figure EBV Y180E;K188A;K188R 87;97;107 92;102;112 BZLF1;BZLF1;BZLF1;BZLF1;BZLF1 121;138;85;95;105 126;143;86;96;106 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. A) Immunoblot demonstrating the effect of EBV replication proteins on late gene expression in BZKO cells expressing Z(S173A), Z(Y180E), and Z(K188A). 2010 PLoS pathogens Figure EBV S173A;Y180E;K188A 118;128;142 123;133;147 BZLF1;BZLF1;BZLF1 116;126;140 117;127;141 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. B) Z(Y180E), but not its revertant, specifically fails to activate EBV late gene expression. 2010 PLoS pathogens Figure EBV Y180E 5 10 BZLF1 3 4 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. BZKO cells were transfected with expression vectors encoding wt ZEBRA, a non-DNA binding mutant Z(R183E), and three replication defective ZEBRA mutants [Z(Y180E), Z(R187K) and Z(K188A)]. 2010 PLoS pathogens Figure EBV R183E;Y180E;R187K;K188A 98;155;165;178 103;160;170;183 BZLF1;BZLF1;BZLF1;BZLF1;BZLF1;BZLF1 64;138;96;153;163;176 69;143;97;154;164;177 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. Chromatin immunoprecipitation of ZEBRA protein from BZKO cells expressing wt ZEBRA, Z(R183E), Z(Y180E) or Z(K188A) and treated with PAA. 2010 PLoS pathogens Figure EBV R183E;Y180E;K188A 86;96;108 91;101;113 BZLF1;BZLF1;BZLF1;BZLF1;BZLF1 33;77;84;94;106 38;82;85;95;107 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. Immunoblot analysis of extracts prepared from BZKO cells transfected with expression vectors encoding wt ZEBRA (Z) and the following ZEBRA mutants: Z(K188A), Z(F193E), and Z(R187K). 2010 PLoS pathogens Figure EBV K188A;F193E;R187K 150;160;174 155;165;179 BZLF1;BZLF1;BZLF1;BZLF1;BZLF1;BZLF1 105;133;112;148;158;172 110;138;113;149;159;173 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. Over-expression of EBV replication proteins partially suppresses the phenotype of Z(S173A) and Z(R187K). 2010 PLoS pathogens Figure EBV S173A;R187K 84;97 89;102 BZLF1;BZLF1 82;95 83;96 24705134 Nuclear translocation and regulation of intranuclear distribution of cytoplasmic poly(A)-binding protein are distinct processes mediated by two Epstein Barr virus proteins. (B) 293 cells were co-transfected with GFP and vector, ZEBRA, Z(S186A), Z(S186E), or Z(N182K). 2014 PloS one Figure EBV S186A;S186E;N182K 64;74;87 69;79;92 BZLF1;BZLF1;BZLF1;BZLF1 55;62;72;85 60;63;73;86 24705134 Nuclear translocation and regulation of intranuclear distribution of cytoplasmic poly(A)-binding protein are distinct processes mediated by two Epstein Barr virus proteins. 293 cells were transfected with pHD1013, or vectors expressing BGLF5, ZEBRA, Z(N182K), or Z(S186E). 2014 PloS one Figure EBV N182K;S186E 79;92 84;97 BGLF5;BZLF1;BZLF1;BZLF1 63;70;77;90 68;75;78;91 25865256 Exosomal sorting of the viral oncoprotein LMP1 is restrained by TRAF2 association at signalling endosomes. (a) Immunofluorescent co-labelling of transfected wtLMP1 or LMP1-C78A (red) in HEK293 cells. 2015 Journal of extracellular vesicles Figure EBV C78A 64 69 LMP1;LMP1 52;60 56;64 25865256 Exosomal sorting of the viral oncoprotein LMP1 is restrained by TRAF2 association at signalling endosomes. (a) Western blotting analysis on LMP1 protein levels in wtLMP1 or LMP1-C78A transfected HEK293 cell and exosome lysates; beta-actin and HSP70 as loading controls. 2015 Journal of extracellular vesicles Figure EBV C78A 70 75 LMP1;LMP1;LMP1 33;58;66 37;62;70 25865256 Exosomal sorting of the viral oncoprotein LMP1 is restrained by TRAF2 association at signalling endosomes. (b, c) Soft-agar assay for anchorage-independent growth of HEK293 cells transfected with wtLMP1, LMP1-C78A, or GFP control (ctrl) construct. 2015 Journal of extracellular vesicles Figure EBV C78A 101 106 LMP1;LMP1 91;97 95;101 25865256 Exosomal sorting of the viral oncoprotein LMP1 is restrained by TRAF2 association at signalling endosomes. (b) Immunofluorescent labelling of endogenous TRAF2 (green) in HEK293 cells transfected with wtLMP1 or LMP1-C78A (red). 2015 Journal of extracellular vesicles Figure EBV C78A 107 112 LMP1;LMP1 95;103 99;107 25865256 Exosomal sorting of the viral oncoprotein LMP1 is restrained by TRAF2 association at signalling endosomes. Cell lysates of HEK293 cells transfected for 24 hours with wtLMP1 or LMP1-C78A, together with an NFkappaB-reporter construct. 2015 Journal of extracellular vesicles Figure EBV C78A 73 78 LMP1;LMP1 61;69 65;73 25865256 Exosomal sorting of the viral oncoprotein LMP1 is restrained by TRAF2 association at signalling endosomes. To the right, reporter assay for LMP1-wt or LMP1-C78A NFkappaB activity. 2015 Journal of extracellular vesicles Figure EBV C78A 48 53 LMP1;LMP1 33;44 37;48 25950714 DNA Damage Signaling Is Induced in the Absence of Epstein-Barr Virus (EBV) Lytic DNA Replication and in Response to Expression of ZEBRA. (A) 293 cells co-transfected with an empty vector (CMV) and a membrane-targeted EGFP-farnesylated construct (mGFP) (A: i) or singly transfected with expression vectors for ZEBRA (A: ii), Z(S186A) (A: iii), Z(N182E) (A: iv), Z(S186E) (A: v), or Z(R183E) (A: vi) were fixed and double-stained for ZEBRA and pATM (S1981); Arrows indicate transfected cells expressing transfected genes or pATM or transfected genes and pATM. 2015 PloS one Figure EBV S186A;N182E;S186E;R183E;S186A;N182E;S186E;R183E 190;209;227;247;189;208;226;246 195;214;232;252;194;213;231;251 BZLF1;BZLF1;BZLF1;BZLF1;BZLF1;BZLF1 172;295;187;206;224;244 177;300;188;207;225;245 25950714 DNA Damage Signaling Is Induced in the Absence of Epstein-Barr Virus (EBV) Lytic DNA Replication and in Response to Expression of ZEBRA. (A) Raji cells infected with an empty vector lentivirus (V), or lentiviruses expressing the wild-type ZEBRA gene (A: i), Z(R179A) (A: ii), or Z(S186A) (A: iii) were fixed and double stained for ZEBRA and pATM. 2015 PloS one Figure EBV R179A;S186A;R179A;S186A 124;145;123;144 129;150;128;149 BZLF1;BZLF1;BZLF1;BZLF1 102;194;121;142 107;199;122;143 25950714 DNA Damage Signaling Is Induced in the Absence of Epstein-Barr Virus (EBV) Lytic DNA Replication and in Response to Expression of ZEBRA. (B) 293 cells were fixed and stained for pATM (S1981) after co-transfection with a membrane-targeted EGFP-farnesylated construct (mGFP) and an empty vector (CMV), or expression vectors for ZEBRA, or Z(S186A), or Z(N182E), or Z(S186E), or Z(R183E). 2015 PloS one Figure EBV S186A;N182E;S186E;R183E 201;214;227;240 206;219;232;245 BZLF1;BZLF1;BZLF1;BZLF1;BZLF1 189;199;212;225;238 194;200;213;226;239 25950714 DNA Damage Signaling Is Induced in the Absence of Epstein-Barr Virus (EBV) Lytic DNA Replication and in Response to Expression of ZEBRA. ATM is phosphorylated upon expression of WT ZEBRA, and ZEBRA mutants Z(R179A), and Z(S186A) in Raji cells. 2015 PloS one Figure EBV R179A;S186A 71;85 76;90 BZLF1;BZLF1;BZLF1;BZLF1 44;55;69;83 49;60;70;84 25950714 DNA Damage Signaling Is Induced in the Absence of Epstein-Barr Virus (EBV) Lytic DNA Replication and in Response to Expression of ZEBRA. CMV, 0.00017 for Z(S186A) vs. 2015 PloS one Figure EBV S186A 19 24 BZLF1 17 18 25950714 DNA Damage Signaling Is Induced in the Absence of Epstein-Barr Virus (EBV) Lytic DNA Replication and in Response to Expression of ZEBRA. CMV, and 0.0013 for Z(N182E) versus CMV. 2015 PloS one Figure EBV N182E 22 27 BZLF1 20 21 25950714 DNA Damage Signaling Is Induced in the Absence of Epstein-Barr Virus (EBV) Lytic DNA Replication and in Response to Expression of ZEBRA. pATM is induced in response to expression of WT ZEBRA, and ZEBRA mutants Z(S186A), and Z(N182E) in 293 cells. 2015 PloS one Figure EBV S186A;N182E 75;89 80;94 BZLF1;BZLF1;BZLF1;BZLF1 48;59;73;87 53;64;74;88 26675171 A single nucleotide polymorphism in the Epstein-Barr virus genome is strongly associated with a high risk of nasopharyngeal carcinoma. Effect of the RPMS1 SNP G155391A on the degradation of RPMS1 protein. 2015 Chinese journal of cancer Figure EBV G155391A 24 32 RPMS1;RPMS1 14;55 19;60 26675171 A single nucleotide polymorphism in the Epstein-Barr virus genome is strongly associated with a high risk of nasopharyngeal carcinoma. Validation of the RPMS1 single nucleotide polymorphism (SNP) G155391A by Sanger sequencing. 2015 Chinese journal of cancer Figure EBV G155391A 61 69 RPMS1 18 23 27009860 ERK2 phosphorylation of EBNA1 serine 383 residue is important for EBNA1-dependent transactivation. Absence of ERK2-directed phosphorylation on hE1 S383A and 526PAS528 double mutant (DM), reduced phosphorylation on I528S mutant. 2016 Oncotarget Figure EBV S383A;I528S 48;115 53;120 27009860 ERK2 phosphorylation of EBNA1 serine 383 residue is important for EBNA1-dependent transactivation. EBNA1-negative BJAB cells were transiently co-transfected with a control vector, EBNA1 S383, S383A, S528, and PAS, along with EBNA1-dependent (POLP2) and -independent (SV40p-RL) reporters. 2016 Oncotarget Figure EBV S383A 93 98 EBNA1;EBNA1;EBNA1 0;81;126 5;86;131 29221111 Nasopharyngeal carcinoma risk prediction via salivary detection of host and Epstein-Barr virus genetic variants. The EBV model factor was G155391A. 2017 Oncotarget Figure EBV G155391A 25 33 33633271 The influence of human genetic variation on Epstein-Barr virus sequence diversity. Significant associations:(A): BALF5, (B): BBRF1, (C): BRLF1:p.Lys316Glu. 2021 Scientific reports Figure EBV K316E 60 71 BBRF1;BALF5;BRLF1 42;30;54 47;35;59 18369464 Methylated DNA recognition during the reversal of epigenetic silencing is regulated by cysteine and serine residues in the Epstein-Barr virus lytic switch protein. In contrast, the C189S mutant is compromised for binding methylated ZRE3, and to a lesser extent ZRE2, but retains wild type affinity towards many unmethylated sites, including ZRE1 (Figures 2 and 3). 2008 PLoS pathogens Discussion EBV C189S 17 22 18369464 Methylated DNA recognition during the reversal of epigenetic silencing is regulated by cysteine and serine residues in the Epstein-Barr virus lytic switch protein. In particular, the model rationalizes why the binding affinity of Zta for unmethylated ZRE3 is lower than for ZRE2, why methylation increases the binding affinity for both sites, why the C189S mutation compromises methyl-ZRE recognition, and why the latter effect is more pronounced for ZRE3 than for ZRE2. 2008 PLoS pathogens Discussion EBV C189S 187 192 BZLF1 66 69 18369464 Methylated DNA recognition during the reversal of epigenetic silencing is regulated by cysteine and serine residues in the Epstein-Barr virus lytic switch protein. More specifically, because ZtaC189S is severely compromised for meZRE3 (but not meZRE2) binding, the inability of this mutant to activate BRLF1 expression in Raji cells suggests that meZRE3 recognition is particularly critical for Rp activation in this cell line (Figure 1). 2008 PLoS pathogens Discussion EBV C189S 30 35 BRLF1;BZLF1 138;27 143;30 18369464 Methylated DNA recognition during the reversal of epigenetic silencing is regulated by cysteine and serine residues in the Epstein-Barr virus lytic switch protein. The stability of the latter contact is predicted to be susceptible to the C189S mutation regardless of CpG methylation status. 2008 PLoS pathogens Discussion EBV C189S 74 79 18369464 Methylated DNA recognition during the reversal of epigenetic silencing is regulated by cysteine and serine residues in the Epstein-Barr virus lytic switch protein. This contact is lost or destabilized by the replacement of C189 by A or S, consistent with the decreased DNA-binding affinity observed for these mutants (Figure 3). 2008 PLoS pathogens Discussion EBV C189S;C189A 59;59 73;73 18369464 Methylated DNA recognition during the reversal of epigenetic silencing is regulated by cysteine and serine residues in the Epstein-Barr virus lytic switch protein. Thus, the C189S mutant provides a highly selective tool to address the relevance of methylated ZRE recognition for the disruption of latency in vivo. 2008 PLoS pathogens Discussion EBV C189S 10 15 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. (ii) The Y180E mutant lacks the ability to stimulate lytic viral DNA synthesis. 2008 Virology Discussion EBV Y180E 9 14 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. 2, 8); 2) in all EA-D-positive cells expressing the ZEBRA mutant Y180E which activates early but not late EBV genes; 3) in cells treated with PAA or ACV and transfected with WT ZEBRA. 2008 Virology Discussion EBV Y180E 65 70 BZLF1;BZLF1;BMRF1 52;177;17 57;182;21 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. 6); and 4) in cells co-expressing the S186A mutant and Rta. 2008 Virology Discussion EBV S186A 38 43 BRLF1 55 58 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. A dramatically different distribution of EA-D in globular replication compartments was observed following transfection of WT ZEBRA or the K188R WT mutant into BZKO, 2089 or D98/HR-1 cells. 2008 Virology Discussion EBV K188R 138 143 BZLF1;BMRF1 125;41 130;45 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. A third distinct class of ZEBRA mutations at position S186 was diffusely distributed in the nucleus in a pattern reminiscent of wild-type protein; however, S186A and S186E did not induce Rta or downstream viral genes, and did not form replication compartments. 2008 Virology Discussion EBV S186A;S186E 156;166 161;171 BZLF1;BRLF1 26;187 31;190 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. A third observation which supports the hypothesis that speckles formed by mutant ZEBRA proteins represent pre-replication sites, as opposed to aberrant recruitment of mutant ZEBRA to pre-existing cellular structures, is that the characteristically distinct speckled distributions of the R179A and Y180E mutations seen in 2089 and BZKO cells were not seen in 293 cells lacking EBV (Fig 5, panels VIII, XII). 2008 Virology Discussion EBV R179A;Y180E 287;297 292;302 BZLF1;BZLF1 81;174 86;179 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. Although the S186A mutant is defective in binding to ZREs which contain a methylated CpG, this mutant retains the ability to bind many other ZRE's as well as, or better than, wild-type or speckle forming mutants (Francis et al.,1997). 2008 Virology Discussion EBV S186A 13 18 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. Co-transfection of Rta with S186A rescued expression of EA-D; however addition of Rta did not alter the diffuse distribution of S186A or EA-D. 2008 Virology Discussion EBV S186A;S186A 28;128 33;133 BMRF1;BMRF1;BRLF1;BRLF1 56;137;19;82 60;141;22;85 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. Furthermore, S186E does not bind DNA, yet is also diffusely distributed throughout the nucleus. 2008 Virology Discussion EBV S186E 13 18 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. Globular EA-D was also observed in D98/HR-1 cells transfected with the R179A early mutant, probably as the result of auto-stimulation of the endogenous WT ZEBRA. 2008 Virology Discussion EBV R179A 71 76 BZLF1;BMRF1 155;9 160;13 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. Globular replication compartments were not observed under conditions known to block late gene expression, including transfection of the late mutant Y180E, treatment with inhibitors of lytic replication, or co-expression of S186A and Rta. 2008 Virology Discussion EBV Y180E;S186A 148;223 153;228 BRLF1 233 236 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. However, the discrete speckled appearance of R179A and Y180E was only observed in EBV-positive 293 cells. 2008 Virology Discussion EBV R179A;Y180E 45;55 50;60 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. Hypotheses Explaining the Diffuse Distribution of Mutant Z(S186A) and Z(S186E) 2008 Virology Discussion EBV S186A;S186E 59;72 64;77 BZLF1;BZLF1 57;70 58;71 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. Hypotheses Explaining the Diffuse Distribution of Mutant Z(S186A) and Z(S186E). 2008 Virology Discussion EBV S186A;S186E 59;72 64;77 BZLF1;BZLF1 57;70 58;71 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. In support of this hypothesis, the mutant R179A remains in a speckled distribution in 2089 cells treated with PAA or ACV. 2008 Virology Discussion EBV R179A 42 47 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. It is likely that other viral or cellular proteins not induced by the combination of S186A and Rta are required for production of the speckled phenotype. 2008 Virology Discussion EBV S186A 85 90 BRLF1 95 98 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. It is possible that S186A, by itself or in combination with Rta and EA-D, does not activate expression of one or more members of the tripartite helicase-primase complex necessary for generation of HSV-1 or EBV pre-replication sites. 2008 Virology Discussion EBV S186A 20 25 BMRF1;BRLF1 68;60 72;63 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. It should also be noted, however, that the roughly textured distribution pattern of the R179A and Y180E mutants in 293 cells differed from the smooth, even distribution seen with wild-type ZEBRA in the same cell type. 2008 Virology Discussion EBV R179A;Y180E 88;98 93;103 BZLF1 189 194 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. K181A, A185V, and R179A) was accompanied by a defect in ZEBRA's capacity to activate Rta or EA-D; whereas other mutants with a speckled distribution. 2008 Virology Discussion EBV K181A;A185V;R179A 0;7;18 5;12;23 BZLF1;BMRF1;BRLF1 56;92;85 61;96;88 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. K188R), found in our earlier study to have no defects in transcriptional activation or DNA replication, had a normal diffuse intra-nuclear distribution of ZEBRA and promoted globular replication compartment formation. 2008 Virology Discussion EBV K188R 0 5 BZLF1 155 160 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. Other ZEBRA mutants, such as R179A and Y180E, may induce expression of these proteins to levels sufficient for speckle formation. 2008 Virology Discussion EBV R179A;Y180E 29;39 34;44 BZLF1 6 11 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. R179A, K181A and A185V arrest the EBV lytic cycle at very early stages, after Rta but before EA-D expresssion. 2008 Virology Discussion EBV R179A;K181A;A185V 0;7;17 5;12;22 BMRF1;BRLF1 93;78 97;81 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. S186A and S186E both differ, however, from other DNA-binding competent ZEBRA mutants in their inability to activate viral gene expression. 2008 Virology Discussion EBV S186A;S186E 0;10 5;15 BZLF1 71 76 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. Since a major difference between S186A and other DNA-binding ZEBRA mutants is an inability to induce expression of Rta, we explored the effect of co-transfection of Rta. 2008 Virology Discussion EBV S186A 33 38 BZLF1;BRLF1;BRLF1 61;115;165 66;118;168 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. The appearance of wild-type, S186A, and K188R mutants was identical in 293 cells with and without EBV. 2008 Virology Discussion EBV S186A;K188R 29;40 34;45 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. The smooth distribution of the S186A and S186E ZEBRA mutants in 2089 cells contrasts with the speckled distribution seen with several other ZEBRA mutants. 2008 Virology Discussion EBV S186A;S186E 31;41 36;46 BZLF1;BZLF1 47;140 52;145 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. The speckled distribution of ZEBRA mutant Y180E was accompanied by two other deficiencies which point to a defect during lytic DNA replication in the assembly or function of the viral core replication complex: (i) 2089 cells transfected with Y180E were incapable of developing mature globular replication compartments, despite having normal expression levels of the polymerase processivity factor, EA-D. 2008 Virology Discussion EBV Y180E;Y180E 42;242 47;247 BZLF1;BMRF1 29;398 34;402 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. Therefore it may be assumed that Z(R179A) does not activate expression or interact properly with BALF5. 2008 Virology Discussion EBV R179A 35 40 BALF5;BZLF1 97;33 102;34 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. These two defects were also characteristic of another late mutant, K188A, which formed speckles similar to Y180E (data not shown). 2008 Virology Discussion EBV K188A;Y180E 67;107 72;112 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. This finding suggests that the R179A speckles are formed prior to the events which are inhibited by PAA and ACV. 2008 Virology Discussion EBV R179A 31 36 18937960 Mutations of amino acids in the DNA-recognition domain of Epstein-Barr virus ZEBRA protein alter its sub-nuclear localization and affect formation of replication compartments. Y180E and K188A) induced expression of EA-D which, however, was not recruited to globular replication compartments. 2008 Virology Discussion EBV Y180E;K188A 0;10 5;15 BMRF1 39 43 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. 6A, C) and targets, such as the BMRF1 promoter, that are activated in synergy by Rta and Z(S186A). 2009 Virology Discussion EBV S186A 91 96 BMRF1;BRLF1;BZLF1 32;81;89 37;84;90 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. A F442A mutant fusion protein did not bind to P-TEFb and was 80% reduced in activity when compared to wild-type VP16 fusion protein. 2009 Virology Discussion EBV F442A 2 7 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. However, Rta (F600A/F605A) mutants which were enhanced in DNA binding were defective in activating direct targets, such as the BMLF1 promoter. 2009 Virology Discussion EBV F600A;F605A 14;20 19;25 BMLF1;BRLF1 127;9 132;12 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. Similarly, Rta (F600A/F605A) is defective in activating both direct targets, such as the BMLF1 and BHLF1 promoters, and indirect targets, such as the BRLF1 promoter. 2009 Virology Discussion EBV F600A;F605A 16;22 21;27 BHLF1;BMLF1;BRLF1;BRLF1 99;89;150;11 104;94;155;14 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. The (F600A/ F605A) mutations that enhance DNA binding do not invariably increase levels of expression of EBV Rta protein. 2009 Virology Discussion EBV F600A;F605A 5;12 10;17 BRLF1 109 112 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. The mutants K527E/K528E enhance DNA binding and promote over-expression of an electrophoretic mobility variant, ORF 50B. 2009 Virology Discussion EBV K527E;K528E 12;18 17;23 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. The ORF50 (K527E/K528E) mutant is defective at activating direct targets, such as the promoter of PAN RNA, and indirect targets, such as the promoter of ORF 57. 2009 Virology Discussion EBV K527E;K528E 11;17 16;22 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. Three alanine substitution point mutants, L597A, I599A and I604A, did not significantly change the transcriptional activity or DNA binding activity of Rta (data not shown). 2009 Virology Discussion EBV L597A;I599A;I604A 42;49;59 47;54;64 BRLF1 151 154 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. While mutations in the terminal phenylalanines of Rta may affect protein-protein interactions required for indirect mechanisms of gene activation, it was unexpected that the Rta (F600A/F605A) mutant was also defective in activating direct target genes, such as BMLF1 and BRLF2. 2009 Virology Discussion EBV F600A;F605A 179;185 184;190 BMLF1;BRLF1;BRLF1 261;50;174 266;53;177 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. Why is enhanced DNA binding by Rta (F600A/F605A) associated with a defect in activating viral target genes in vivo? 2009 Virology Discussion EBV F605A;F600A 42;36 47;41 BRLF1 31 34 19232420 Two phenylalanines in the C-terminus of Epstein-Barr virus Rta protein reciprocally modulate its DNA binding and transactivation function. Why is enhanced DNA binding by Rta (F600A/F605A) associated with a defect in activating viral target genes in vivo. 2009 Virology Discussion EBV F600A;F605A 36;42 41;47 19325883 Methylation-dependent binding of the epstein-barr virus BZLF1 protein to viral promoters. As previously reported, we found that the Z(C189S) mutant induces lytic infection in latently infected 293 cells almost as well as wild-type Z, perhaps reflecting our previous finding that some Rp ZREs are unmethylated in this cell type. 2009 PLoS pathogens Discussion EBV C189S 44 49 BZLF1;BZLF1 42;141 43;142 19325883 Methylation-dependent binding of the epstein-barr virus BZLF1 protein to viral promoters. Consistent with its methylation-dependent binding defect, the Z(S186A) mutant is unable to activate the methylated Nap reporter construct in vivo, or to induce Na expression from the methylated viral genome in latently infected cells even in the presence of a co-transfected R expression vector. 2009 PLoS pathogens Discussion EBV S186A 64 69 BZLF1 62 63 19325883 Methylation-dependent binding of the epstein-barr virus BZLF1 protein to viral promoters. Furthermore, the Z(S186A) mutant cannot disrupt viral latency when transfected into latently infected cells, and this phenotype is at least partially reversed when the R protein is supplied in trans, expressed under the control of a constitutively active promoter. 2009 PLoS pathogens Discussion EBV S186A 19 24 BZLF1 17 18 19325883 Methylation-dependent binding of the epstein-barr virus BZLF1 protein to viral promoters. However, the Z(C189S) mutant is not predicted to have these interactions. 2009 PLoS pathogens Discussion EBV C189S 15 20 BZLF1 13 14 19325883 Methylation-dependent binding of the epstein-barr virus BZLF1 protein to viral promoters. In all of our models, Ser186 appears to play a central role in bridging the hydrogen bond networks, consistent with the observation that Z(S186A) is impaired for binding to all four known methylated ZREs in EBV. 2009 PLoS pathogens Discussion EBV S186A 139 144 BZLF1 137 138 19325883 Methylation-dependent binding of the epstein-barr virus BZLF1 protein to viral promoters. In our experiments, we confirmed that Z(C189S) is highly impaired for binding to the methylated form of the Rp ZRE3 site, as well as the Nap ZRE1 site, but much less impaired for binding to the methylated forms of Nap ZRE2 and Rp ZRE2. 2009 PLoS pathogens Discussion EBV C189S 40 45 BZLF1 38 39 19325883 Methylation-dependent binding of the epstein-barr virus BZLF1 protein to viral promoters. In this paper, we have shown that the Z mutant, Z(S186A), is severely impaired for binding to each of the four known methylated ZRE sites in EBV. 2009 PLoS pathogens Discussion EBV S186A 50 55 BZLF1;BZLF1 38;48 39;49 19325883 Methylation-dependent binding of the epstein-barr virus BZLF1 protein to viral promoters. Our finding that Z(C189S) binds to some methylation-dependent ZREs more efficiently than to the Rp ZRE3 site may reflect the absence of a thymine at the -2' position in these other ZREs. 2009 PLoS pathogens Discussion EBV C189S 19 24 BZLF1 17 18 19325883 Methylation-dependent binding of the epstein-barr virus BZLF1 protein to viral promoters. recently reported that Z(C189S) is defective in binding to the methylated Rp ZRE3 site (although this defect was not redox dependent), and based on this finding proposed that Z Cys189 directly contributes to Z binding to at least some methylated ZREs. 2009 PLoS pathogens Discussion EBV C189S 25 30 BZLF1;BZLF1;BZLF1 23;175;208 24;176;209 19325883 Methylation-dependent binding of the epstein-barr virus BZLF1 protein to viral promoters. The finding that the Z(S186A) mutant is defective not only for BRLF1 (R) gene activation, but also for BRRF1 (Na) gene activation, suggests that loss of both R and Na protein expression may contribute to its phenotype. 2009 PLoS pathogens Discussion EBV S186A 23 28 BRLF1;BRRF1;BZLF1 63;103;21 68;108;22 19325883 Methylation-dependent binding of the epstein-barr virus BZLF1 protein to viral promoters. We and others have previously shown that a Z(S186A) mutant binds very poorly to the methylated forms of Rp ZRE2 and Rp ZRE3, even though this alteration does not affect Z binding to the consensus (and unmethylated) AP1 motif. 2009 PLoS pathogens Discussion EBV S186A 45 50 BZLF1;BZLF1 43;169 44;170 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. Z(S173A), also abolishes viral replication, while another substitution that maintains DNA binding. 2010 PLoS pathogens Discussion EBV S173A 2 7 BZLF1 0 1 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. Z(S173D), has no effect on viral replication. 2010 PLoS pathogens Discussion EBV S173D 2 7 BZLF1 0 1 20808903 A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. ZEBRA RD mutants with compromised DNA binding activity can be divided into two subclasses: the phosphorylation site mutants, Z(S173A) and Z(S167A/S173A), and the basic domain mutants, Z(Y180E), Z(R187K) and Z(K188A). 2010 PLoS pathogens Discussion EBV S173A;S173A;S167A;Y180E;R187K;K188A 127;146;140;186;196;209 132;151;145;191;201;214 BZLF1;BZLF1;BZLF1;BZLF1;BZLF1;BZLF1 0;125;138;184;194;207 5;126;139;185;195;208 20849661 Conserved mutation of Epstein-Barr virus-encoded BamHI-A Rightward Frame-1 (BARF1) gene in Indonesian nasopharyngeal carcinoma. Another NPC tumor line derived from North-African origin, C15, even though demonstrating the V29A codon conversion, was also separated from most of the Indonesian NPC samples. 2010 Infectious agents and cancer Discussion EBV V29A 93 97 Nasopharyngeal carcinoma;Nasopharyngeal carcinoma 163;8 166;11 20849661 Conserved mutation of Epstein-Barr virus-encoded BamHI-A Rightward Frame-1 (BARF1) gene in Indonesian nasopharyngeal carcinoma. Five mutations led to amino acid changes, mostly yielding conserved mutations of V29A (valine to alanine) and H130R (histidine to arginine). 2010 Infectious agents and cancer Discussion EBV V29A;H130R 81;110 85;115 20849661 Conserved mutation of Epstein-Barr virus-encoded BamHI-A Rightward Frame-1 (BARF1) gene in Indonesian nasopharyngeal carcinoma. Furthermore, BARF1 variants with 2 amino acid changes (V29A and H130R) most commonly detected in EBV isolates from the NPC group which indicates this to be the dominant strain in Indonesian NPC. 2010 Infectious agents and cancer Discussion EBV V29A;H130R 55;64 59;69 BARF1 13 18 Nasopharyngeal carcinoma;Nasopharyngeal carcinoma 190;119 193;122 20849661 Conserved mutation of Epstein-Barr virus-encoded BamHI-A Rightward Frame-1 (BARF1) gene in Indonesian nasopharyngeal carcinoma. Only nucleotide mutation on 165589 (T to C) was similar to most of the sequences in our isolates. 2010 Infectious agents and cancer Discussion EBV T165589C 28 43 20849661 Conserved mutation of Epstein-Barr virus-encoded BamHI-A Rightward Frame-1 (BARF1) gene in Indonesian nasopharyngeal carcinoma. Our preliminary data indicate that the Indonesian variant BARF1 (V29A and H130R) is rapidly secreted from human epithelial cells, has a stable hexameric structure and binds M-CSF (CSF-1) with high affinity (Hoebe et al., unpublished data). 2010 Infectious agents and cancer Discussion EBV V29A;H130R 65;74 69;79 BARF1 58 63 20849661 Conserved mutation of Epstein-Barr virus-encoded BamHI-A Rightward Frame-1 (BARF1) gene in Indonesian nasopharyngeal carcinoma. reported variants of BARF1 gene on EBV cell lines from EBV-associated T/NK-cell lymphoma showing change of G to A at the position of 165554, change of T to C at 165589, and change of T to C at 165545. 2010 Infectious agents and cancer Discussion EBV T165589C;T165545C 151;183 167;199 BARF1 21 26 NK/T-cell lymphoma 70 88 21560118 Transmembrane peptides used to investigate the homo-oligomeric interface and binding hotspot of latent membrane protein 1. Our results are consistent with a model in which the oligomeric state of LMP-1 is trimeric, and that of LMP-1 D150A is dimeric. 2011 Biopolymers Discussion EBV D150A 110 115 LMP1;LMP1 73;104 78;109 21560118 Transmembrane peptides used to investigate the homo-oligomeric interface and binding hotspot of latent membrane protein 1. Replacement of D150 with alanine in TM5 abolishes trimerization and the resulting peptide (TM5 D150A) is primarily dimeric. 2011 Biopolymers Discussion EBV D150A 95 100 21560118 Transmembrane peptides used to investigate the homo-oligomeric interface and binding hotspot of latent membrane protein 1. Substitution of D150 with alanine in full-length LMP-1 resulted in significant attenuation of NFkappaB activation, suggesting that LMP-1 D150A adopts a different oligomeric state than does LMP-1. 2011 Biopolymers Discussion EBV D150A 137 142 LMP1;LMP1;LMP1 49;131;189 54;136;194 22348267 Sequence analysis of Epstein-Barr virus EBNA-2 gene coding amino acid 148-487 in nasopharyngeal and gastric carcinomas. A 51bp deletion at nucleotide 49102 was detected in LCLs from New Guinea as well as two German patients with fatal lymphoproliferative disease. 2012 Virology journal Discussion EBV del 49102 7 35 Lymphoproliferative disease 115 142 22348267 Sequence analysis of Epstein-Barr virus EBNA-2 gene coding amino acid 148-487 in nasopharyngeal and gastric carcinomas. In this domain, residues (I438L, E476G, P484H and I486T) were only detected in the NPC samples (Figure 1 and Table 1) and the GD1 does not have these mutations. 2012 Virology journal Discussion EBV I438L;E476G;P484H;I486T 26;33;40;50 31;38;45;55 Nasopharyngeal carcinoma 83 86 22348267 Sequence analysis of Epstein-Barr virus EBNA-2 gene coding amino acid 148-487 in nasopharyngeal and gastric carcinomas. Of the three common mutations, amino acid mutation R163M and silent mutation c48998a were previously identified in 13 Korean isolates, 18 of 33 oral squamous cell carcinoma cases in Okinawa, Japan and 6 human immunodeficiency virus-infected patients and the NPC samples in Hong Kong or Canton. 2012 Virology journal Discussion EBV C48998A;R163M 77;51 84;56 EBV-HIV coinfections;Squamous cell carcinoma of head and neck;Nasopharyngeal carcinoma 203;144;258 240;172;261 22348267 Sequence analysis of Epstein-Barr virus EBNA-2 gene coding amino acid 148-487 in nasopharyngeal and gastric carcinomas. The mutation R163M, which was located in the self-association (aa 148-214) domain of EBNA-2, was detected in all samples. 2012 Virology journal Discussion EBV R163M 13 18 EBNA2 85 91 22348267 Sequence analysis of Epstein-Barr virus EBNA-2 gene coding amino acid 148-487 in nasopharyngeal and gastric carcinomas. The silent mutation t49613a was detected in W91, an EBV A isolate from an African case of Burkitt's lymphoma and GD1, from a southern Chinese patient. 2012 Virology journal Discussion EBV T49613A 20 27 Burkitt lymphoma 90 108 22348267 Sequence analysis of Epstein-Barr virus EBNA-2 gene coding amino acid 148-487 in nasopharyngeal and gastric carcinomas. Then the mutation R163M may be a common mutation and have some effects on transformation of the EBNA-2 gene. 2012 Virology journal Discussion EBV R163M 18 23 EBNA2 96 102 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. Amino acid change F144I is present in variants that cluster with CAO in a phylogenetic analysis and that have the ability to activate NF-kappaB at high levels. 2012 PloS one Discussion EBV F144I 18 23 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. An additional amino acid change associated with enhanced NF-kappaB activation is F106Y. 2012 PloS one Discussion EBV F106Y 81 86 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. Another amino acid change associated with enhanced NF-kappaB activation is I124V. 2012 PloS one Discussion EBV I124V 75 80 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. EBV type 2 LMP1 AG876 does not carry the mutation F144I but carry a 10 amino acid deletion indicating that F144I and the 10 amino acid deletion do not always segregate together. 2012 PloS one Discussion EBV F144I;F144I 50;107 55;112 LMP1 11 15 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. F106Y is also present in LMP1 AG876. 2012 PloS one Discussion EBV F106Y 0 5 LMP1 25 29 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. F106Y was shown to be present in the population at a high frequency. 2012 PloS one Discussion EBV F106Y 0 5 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. F144I was also reported in LMP1 variants isolated from several malignancies that do not carry the deletion, such as the European group C, and the subgroup Ch2 and AL. 2012 PloS one Discussion EBV F144I 0 5 LMP1 27 31 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. However, since F106Y is also present in variants such as P1 that induced NF-kappaB activation levels close to B95-8 LMP1, the effect of this polymorphism on signaling is likely to be modulated by one or several polymorphisms yet to be mapped. 2012 PloS one Discussion EBV F106Y 15 20 LMP1 116 120 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. Most interestingly, we observed a high frequency of the polymorphism F144I in published sequences of LMP1 from EBV associated tumors: 5/5 variants isolated from Vietnamese patients with NPC, 21/21 variants isolated from patients with NPC in the southern China, 7/7 variants isolated from patients with nasal NK/T-cell lymphoma, 5/5 variants from NPC in Hong Kong, and in 10/12 variants isolated from salivary gland lymphoepithelial carcinoma. 2012 PloS one Discussion EBV F144I 69 74 LMP1 101 105 Nasopharyngeal carcinoma;Nasopharyngeal carcinoma;NK/T-cell lymphoma;Nasopharyngeal carcinoma;Ovarian epithelial carcinoma 186;234;302;346;400 189;237;326;349;441 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. Overall the pilot clinical study on the potential association of polymorphisms I124V/I152L and F144I/D150A/L151I with HL demonstrated the feasibility and interest of such an approach, even if the statistical power was too low to draw a definitive conclusion, which is a major limit of this study. 2012 PloS one Discussion EBV I124V;I152L;F144I;D150A;L151I 79;85;95;101;107 84;90;100;106;112 Hodgkin lymphoma 118 120 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. Polymorphisms I124V/I152L and F144I/D150A/L151I were chosen as markers of enhanced NF-kappaB activation in a pilot epidemiological study within the SHCS. 2012 PloS one Discussion EBV I124V;I152L;F144I;D150A;L151I 14;20;30;36;42 19;25;35;41;47 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. Taken together, our results showed that enhanced NF-kappaB activation resulted from single amino acid changes in the transmembrane segments 4 and 5 of the protein: F106Y, I124V and F144I. 2012 PloS one Discussion EBV F106Y;I124V;F144I 164;171;181 169;176;186 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. The back mutation Y106F in variants 7795, 7815, 7918, 7821 and 7948 led to a significant down modulation of NF-kappaB activation, demonstrating that F106Y is the polymorphism responsible for the increased signaling by these variants. 2012 PloS one Discussion EBV Y106F;F106Y 18;149 23;154 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. The linked polymorphisms _ENREF_33F144I/D150A/L151I are distinctive features of this group of variants. 2012 PloS one Discussion EBV D150A;L151I;F144I 40;46;34 45;51;39 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. This group of variants is more closely related to China1 than to the other LMP1 strains with F144I described by Edwards et al. 2012 PloS one Discussion EBV F144I 93 98 LMP1 75 79 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. This polymorphism always segregates with I152L and was not previously described. 2012 PloS one Discussion EBV I152L 41 46 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. We found that the introduction of mutation F106Y in B95-8 LMP1 led to enhanced NF-kappaB activation compared to wild type B95-8 LMP1. 2012 PloS one Discussion EBV F106Y 43 48 LMP1;LMP1 58;128 62;132 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. We identified F144I as responsible for the enhanced NF-kappaB by variant A2, which is a close relative of CAO and showed that all the variants we isolated in our study that carry isoleucine at position 144 display the same phenotype. 2012 PloS one Discussion EBV F144I 14 19 22384168 Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Kappab activation. We observed that I124V/I152L and F144I/D150A/L151I, combined, were found in virus from more than 50% of the participants from each group. 2012 PloS one Discussion EBV I124V;I152L;F144I;D150A;L151I 17;23;33;39;45 22;28;38;44;50 22590638 Genomic sequencing and comparative analysis of Epstein-Barr virus genome isolated from primary nasopharyngeal carcinoma biopsy. HKNPC1, GD1 and GD2 strains shared the Cp mutation (11404 C>T), whereas only GD2 and HKNPC1 shared the Qp mutation (50134 G>C). 2012 PloS one Discussion EBV C11404T;G50134C 52;116 61;125 22590638 Genomic sequencing and comparative analysis of Epstein-Barr virus genome isolated from primary nasopharyngeal carcinoma biopsy. Non-synonymous mutations in glycoprotein genes BLLF1 (79,265 C>G) and BALF4 (157,568 C>T) were found common in HKNPC1, GD1 and GD2. 2012 PloS one Discussion EBV C79265G;C157568T 54;77 64;88 BALF4;BLLF1 70;47 75;52 22590638 Genomic sequencing and comparative analysis of Epstein-Barr virus genome isolated from primary nasopharyngeal carcinoma biopsy. These mutations cause amino acid changes at the CR2 receptor binding site of gp350 (E201Q) and at the furin cleavage site of gB (D433N) proteins, respectively. 2012 PloS one Discussion EBV E201Q;D433N 84;129 89;134 24016332 Identification of a novel variant of LMP-1 of EBV in patients with endemic Burkitt lymphoma in western Kenya. We are unaware of any previous studies describing the characteristic G318K mutation of the K variant sequence. 2013 Infectious agents and cancer Discussion EBV G318K 69 74 24705134 Nuclear translocation and regulation of intranuclear distribution of cytoplasmic poly(A)-binding protein are distinct processes mediated by two Epstein Barr virus proteins. A ZEBRA mutant, Z(S186E), that is deficient in translocation of PABPC did not by itself inhibit expression of GFP in the shutoff reporter assay. 2014 PloS one Discussion EBV S186E 18 23 BZLF1;BZLF1 2;16 7;17 24705134 Nuclear translocation and regulation of intranuclear distribution of cytoplasmic poly(A)-binding protein are distinct processes mediated by two Epstein Barr virus proteins. The Z(S186E) mutant that is deficient in PABPC translocation does not inhibit GFP expression and is impaired in shutoff of protein synthesis. 2014 PloS one Discussion EBV S186E 6 11 BZLF1 4 5 25865256 Exosomal sorting of the viral oncoprotein LMP1 is restrained by TRAF2 association at signalling endosomes. One question remains: whether palmitoylation could actually promote LMP1 anchoring in late-endosomal membranes, as not all LMP1-C78A is retained peri-nuclearly. 2015 Journal of extracellular vesicles Discussion EBV C78A 127 132 LMP1;LMP1 68;123 72;127 25950714 DNA Damage Signaling Is Induced in the Absence of Epstein-Barr Virus (EBV) Lytic DNA Replication and in Response to Expression of ZEBRA. The finding that ZEBRA mutants Z(S186E) and Z(R183E), which are deficient in DNA binding (Table 1), were also deficient in inducing foci of ATM phosphorylation (Fig 10) points to a possible role for DNA or chromatin interaction in ZEBRA-induced DNA damage signaling. 2015 PloS one Discussion EBV S186E;R183E 33;46 38;51 BZLF1;BZLF1;BZLF1;BZLF1 17;231;31;44 22;236;32;45 25950714 DNA Damage Signaling Is Induced in the Absence of Epstein-Barr Virus (EBV) Lytic DNA Replication and in Response to Expression of ZEBRA. Z(N182E), a ZEBRA mutant which cannot bind ZIIIB sites (Table 1 and) but binds AP1 sequences comparably to wild type ZEBRA and Z(S186A) (S5 Fig), induced foci of phosphorylated ATM unlike other ZIIIB binding deficient ZEBRA mutants used in this study (Fig 10). 2015 PloS one Discussion EBV N182E;S186A 2;129 7;134 BZLF1;BZLF1;BZLF1;BZLF1;BZLF1 12;117;218;0;127 17;122;223;1;128 26337172 Sequence analysis of Epstein-Barr virus (EBV) early genes BARF1 and BHRF1 in NK/T cell lymphoma from Northern China. Despite the scarcity of mutations with only seven amino acid mutations exhibited in nine samples, the relatively hot mutational spot was V29A detected in 5 of 47 (10.6 %) samples, accompanied with one or more of four silent mutations (165575 nt C T, 165698 nt C T, 165768 nt T C, 165944 nt C T). 2015 Virology journal Discussion EBV V29A 137 141 26337172 Sequence analysis of Epstein-Barr virus (EBV) early genes BARF1 and BHRF1 in NK/T cell lymphoma from Northern China. Furthermore, the V29A subtype showed a higher prevalence in NPC (25.3 %, 20/79) than in EBVaGC (0/45) and healthy donors (4.3 %, 2/46) in Northern China. 2015 Virology journal Discussion EBV V29A 17 21 Nasopharyngeal carcinoma;Gastric carcinoma 60;88 63;94 26337172 Sequence analysis of Epstein-Barr virus (EBV) early genes BARF1 and BHRF1 in NK/T cell lymphoma from Northern China. However, V29A subtype in Indonesian NPC isolates showed higher frequency (78.6 %, 44/56) than in NPC isolates from NPC non-endemic areas including Northern China (25.3 %, 20/79), Italy (0/14), and in non-NPC isolates from Europe (33.3 %, 5/15) and Northern China (2.2 %, 2/91). 2015 Virology journal Discussion EBV V29A 9 13 Nasopharyngeal carcinoma;Nasopharyngeal carcinoma;Nasopharyngeal carcinoma;Nasopharyngeal carcinoma 36;97;115;204 39;100;118;207 26337172 Sequence analysis of Epstein-Barr virus (EBV) early genes BARF1 and BHRF1 in NK/T cell lymphoma from Northern China. In Indonesia, V29A mutants was the most dominant in NPC (80.3 % of all NPC), but it was statistically insignificant compared to the mutation rate of 40.0 % in LCLs from healthy EBV carriers (p = 0.074). 2015 Virology journal Discussion EBV V29A 14 18 Nasopharyngeal carcinoma;Nasopharyngeal carcinoma 52;71 55;74 26337172 Sequence analysis of Epstein-Barr virus (EBV) early genes BARF1 and BHRF1 in NK/T cell lymphoma from Northern China. In Northern China, amino acid mutation L88V has been found in 26 of 39 (66.7 %) NPC, 34 (85.0 %) of 40 EBVaGC, and 41 (77.4 %) of 53 TW samples from healthy donors. 2015 Virology journal Discussion EBV L88V 39 43 Nasopharyngeal carcinoma;Gastric carcinoma 80;103 83;109 26337172 Sequence analysis of Epstein-Barr virus (EBV) early genes BARF1 and BHRF1 in NK/T cell lymphoma from Northern China. reported that the V29A mutation in the transforming domain are not considered to change the structure of the protein, so may have little effect on its function. 2015 Virology journal Discussion EBV V29A 18 22 26337172 Sequence analysis of Epstein-Barr virus (EBV) early genes BARF1 and BHRF1 in NK/T cell lymphoma from Northern China. These mutations were highly conservative with L88V detected in 41 (41/53, 77.4 %) samples. 2015 Virology journal Discussion EBV L88V 46 50 26337172 Sequence analysis of Epstein-Barr virus (EBV) early genes BARF1 and BHRF1 in NK/T cell lymphoma from Northern China. Though alpha4 helix carried the dominant mutation L88V in 41 samples (77.4 %), considering the similar properties of valine and leucine: both are neutral and hydrophobic, this substitution was not expected to have any effects. 2015 Virology journal Discussion EBV L88V 50 54 26337172 Sequence analysis of Epstein-Barr virus (EBV) early genes BARF1 and BHRF1 in NK/T cell lymphoma from Northern China. We have detected V29A BARF1 subtytpe in 20 of 79 (25.3 %) NPC, 0 of 45 (0 %) EBVaGC and 2 of 46 (4.3 %) TWs from healthy donors. 2015 Virology journal Discussion EBV V29A 17 21 BARF1 22 27 Nasopharyngeal carcinoma;Gastric carcinoma 58;77 61;83 26675171 A single nucleotide polymorphism in the Epstein-Barr virus genome is strongly associated with a high risk of nasopharyngeal carcinoma. In this multi-stage association study with a large sample size, we identified an EBV genomic sequence variation represented by RPMS1 SNP G155391A that was associated with a high risk of NPC. 2015 Chinese journal of cancer Discussion EBV G155391A 137 145 RPMS1 127 132 Nasopharyngeal carcinoma 186 189 26675171 A single nucleotide polymorphism in the Epstein-Barr virus genome is strongly associated with a high risk of nasopharyngeal carcinoma. RPMS1 SNP G155391A was enriched in NPC patients but was not associated with other malignancies; these results support the hypothesis that there is a highly oncogenic EBV subtype specifically leading to NPC risk. 2015 Chinese journal of cancer Discussion EBV G155391A 10 18 RPMS1 0 5 Nasopharyngeal carcinoma;Nasopharyngeal carcinoma 202;35 205;38 26675171 A single nucleotide polymorphism in the Epstein-Barr virus genome is strongly associated with a high risk of nasopharyngeal carcinoma. The frequency of RPMS1 SNP G155391A was significantly associated with the NPC incidence, and higher frequencies were observed in the NPC endemic areas, suggesting that RPMS1 SNP G155391A might explain the different incidences of NPC worldwide. 2015 Chinese journal of cancer Discussion EBV G155391A;G155391A 27;178 35;186 RPMS1;RPMS1 17;168 22;173 Nasopharyngeal carcinoma;Nasopharyngeal carcinoma;Nasopharyngeal carcinoma 133;229;74 136;232;77 26675171 A single nucleotide polymorphism in the Epstein-Barr virus genome is strongly associated with a high risk of nasopharyngeal carcinoma. The identification of the high-risk RPMS1 SNP G155391A for NPC emphasizes that the contribution of EBV strain variation to virus-associated malignancies should not be ignored. 2015 Chinese journal of cancer Discussion EBV G155391A 46 54 RPMS1 36 41 Nasopharyngeal carcinoma;EBV-related malignancy 59;123 62;152 26675171 A single nucleotide polymorphism in the Epstein-Barr virus genome is strongly associated with a high risk of nasopharyngeal carcinoma. The identification of the high-risk RPMS1 SNP G155391A suggests that we should consider the contribution of EBV variations to the applications of serological EBV markers, such as DNA in NPC monitoring and prognostication. 2015 Chinese journal of cancer Discussion EBV G155391A 46 54 RPMS1 36 41 Nasopharyngeal carcinoma 186 189 27009860 ERK2 phosphorylation of EBNA1 serine 383 residue is important for EBNA1-dependent transactivation. S393 is phosphorylated by CDK/cyclin complexes, and the S393A mutation was previously described as having no effect on transcription activity and only 60% persistence. 2016 Oncotarget Discussion EBV S393A 56 61 27009860 ERK2 phosphorylation of EBNA1 serine 383 residue is important for EBNA1-dependent transactivation. Therefore, it is equally possible that other kinases, such as viral BGLF4, CDKs, or CKs, may phosphorylate S383A in vivo. 2016 Oncotarget Discussion EBV S383A 107 112 BGLF4 68 73 27009860 ERK2 phosphorylation of EBNA1 serine 383 residue is important for EBNA1-dependent transactivation. To this end, the S385A mutation has lower binding affinity for the nuclear import adaptor protein, Importin subunit alpha 5. 2016 Oncotarget Discussion EBV S385A 17 22 29221111 Nasopharyngeal carcinoma risk prediction via salivary detection of host and Epstein-Barr virus genetic variants. Our independent analyses of the G155391A variant in EBV RPMS1 in tumor biopsy and throat washing from study population 1 and in saliva from study population 3 also consistently revealed its strong association with NPC. 2017 Oncotarget Discussion EBV G155391A 32 40 RPMS1 56 61 Nasopharyngeal carcinoma 214 217 29221111 Nasopharyngeal carcinoma risk prediction via salivary detection of host and Epstein-Barr virus genetic variants. Thus, G155391A in EBV RPMS1 could serve as a valuable indicator for high risk of NPC in southern China. 2017 Oncotarget Discussion EBV G155391A 6 14 RPMS1 22 27 Nasopharyngeal carcinoma 81 84 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. Here, we utilized a PBM platform to evaluate the sequence-specificity of Zta and four mutants Zta(C189S), Zta(C189T), Zta(C189A), and Zta(C189V) to four types of dsDNA containing either cytosine on both strands, 5mC or 5hmC on one DNA strand, or 5mCG. 2018 Biochemical and biophysical research communications Discussion EBV C189S;C189T;C189A;C189V 98;110;122;138 103;115;127;143 BZLF1;BZLF1;BZLF1;BZLF1;BZLF1 73;94;106;118;134 76;97;109;121;137 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. Our structural analysis indicates that additional hydrogen bonds between polar groups of the side chains of serine or threonine with the DNA backbone stabilize Zta(C189S) or Zta(C189T) binding, explaining the increased binding of these mutants to preferentially bound sites, such as the TRE. 2018 Biochemical and biophysical research communications Discussion EBV C189S;C189T 164;178 169;183 BZLF1;BZLF1 160;174 163;177 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. The differences between Zta and Zta(C189S) in binding DNA underscores the ability of the PBM platform to reveal changes in sequence-specific DNA binding. 2018 Biochemical and biophysical research communications Discussion EBV C189S 36 41 BZLF1;BZLF1 24;32 27;35 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. Zta(C189A) and Zta(C189V) bound DNA but had reduced sequence specificity to all four types of dsDNA examined. 2018 Biochemical and biophysical research communications Discussion EBV C189A;C189V 4;19 9;24 BZLF1;BZLF1 0;15 3;18 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. Zta(C189S) and Zta(C189T) also bound DNA(5mC C), DNA(5hmC C), DNA(5mCG) similarly to Zta, with reductions in binding to several 8-mers containing these modified cytosines, suggesting that C189 plays a general role in stabilizing or promoting binding to methylated DNA sequences. 2018 Biochemical and biophysical research communications Discussion EBV C189S;C189T 4;19 9;24 BZLF1;BZLF1;BZLF1 0;15;85 3;18;88 29772230 Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. Zta(C189S) and Zta(C189T) bound the TRE motif (TGAG/CTCA) stronger than Zta while binding to all other sequences was reduced. 2018 Biochemical and biophysical research communications Discussion EBV C189S;C189T 4;19 9;24 BZLF1;BZLF1;BZLF1 0;15;72 3;18;75 33633271 The influence of human genetic variation on Epstein-Barr virus sequence diversity. We identified two EBV genes (BALF5, BBRF1) and one EBV amino acid (BRLF1 p.Lys316Glu) as associated with three regions of the human genome, spanning altogether 25 SNPs. 2021 Scientific reports Discussion EBV K316E 73 84 BBRF1;BALF5;BRLF1 36;29;67 41;34;72 34567789 A comprehensive analysis of genetic diversity of EBV reveals potential high-risk subtypes associated with nasopharyngeal carcinoma in China. Although two variates (BALF2 V317M and RPMS1 D51E) had been reported, the newly identified BNRF1 variant (V1222I) yields the highest OR. 2021 Virus evolution Discussion EBV V317M;D51E;V1222I 29;45;106 34;49;112 BNRF1;RPMS1;BALF2 91;39;23 96;44;28 34567789 A comprehensive analysis of genetic diversity of EBV reveals potential high-risk subtypes associated with nasopharyngeal carcinoma in China. It is noteworthy that the genetic variation of BALF2 V317M and BNRF1 V1222I showed the strong evidence of positive selection, which possibly caused by the viral evolution to avoid host immune surveillance. 2021 Virus evolution Discussion EBV V317M;V1222I 53;69 58;75 BNRF1;BALF2 63;47 68;52 34567789 A comprehensive analysis of genetic diversity of EBV reveals potential high-risk subtypes associated with nasopharyngeal carcinoma in China. There seems to be two tendencies, BNRF1 V1222I showing positive association with NPC only presented in China, while five others enrolling lower risks was relatively more frequent in non-endemic areas. 2021 Virus evolution Discussion EBV V1222I 40 46 BNRF1 34 39 Nasopharyngeal carcinoma 81 84