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Gene Review

BKRF1  -  EBNA-1 protein

Human herpesvirus 4

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Disease relevance of EBNA-1

  • Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA-1) is essential for replication of episomal EBV DNAs and maintenance of latency [1].
  • Extranodal, nasal NK/T-cell lymphomas are regularly Epstein-Barr virus (EBV)-positive, with a type II latency pattern, expressing thus EBNA-1 and LMP1 [2].
  • For example, endemic Burkitt lymphoma (BL) classically presents as a monoclonal, c-myc-translocation-positive tumor in which every cell carries EBV as an EBNA1-only (Latency I) infection; such homogeneity among EBV-positive cells, and the lack of EBV-negative comparators, hampers attempts to understand EBV's role in BL pathogenesis [3].
  • We have raised a murine CTL line that recognizes an epitope within EBNA-1 by immunizing mice with a vaccinia virus encoding a COOH-terminal EBNA-1 fragment [4].
  • We also show that EBNA-1 can bind exon sequences derived from its own RNA expressed from the Fp promoter, as found in Burkitt's lymphoma-related cells and in nasopharyngeal carcinomas [5].

Psychiatry related information on EBNA-1

  • Synergy between Myc and EBNA-1 in lymphomagenesis was revealed in a cross breed study where co-expression of transgenic myc and EBNA-1 led to a tumor latency period reduced significantly in some crosses [6].

High impact information on EBNA-1


Chemical compound and disease context of EBNA-1

  • To examine the role of EBV nuclear antigen (EBNA) 3C in the proliferation of LCLs, we established LCLs infected with an EBV recombinant that expresses EBNA3C with a C-terminal fusion to a 4-hydroxytamoxifen (4HT)-dependent mutant estrogen receptor, E3C-HT [10].
  • The EBV antigen contains three potential 'RGG' motifs located around an internal glycine/alanine-rich repetitive sequence in the protein, and outside the region of EBNA-1 mapped previously as essential for viral DNA replication and other functionally defined properties [5].
  • EBV mutants lacking almost all of internal repeat 3, which encode a repetitive glycine and alanine domain of EBNA-1, were generated in the same way and found to immortalize B cells normally [11].
  • A cDNA expression vector containing the element oriP and the sequence encoding the Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA-1) as well as the hygromycin B-resistance dominant marker gene has been constructed [12].
  • Some patients with SLE develop antibodies that recognize a proline rich epitope in the ribonucleoprotein Sm B/B that is similar to an epitope in EBNA-1, a major nuclear antigen of EBV [13].

Biological context of EBNA-1

  • The results suggest dynamic nuclear transport control of phosphorylated EBNA-1 proteins, although the nuclear localization level of EBNA-1 that binds to cellular chromosomes and chromatin seems unchanged [1].
  • However, transfection analyses of GFP-EBNA1 mutants with the Ser-to-Ala substitution causing reduced nuclear import efficiency did not result in a decrease in the nuclear accumulation level of EBNA-1 [1].
  • Here, we examined the effects on nuclear translocation of Ser phosphorylation of the EBNA-1 nuclear localization signal (NLS) sequence, 379Lys-Arg-Pro-Arg-Ser-Pro-Ser-Ser386 [1].
  • Type I latency and type III latency can be distinguished by the expression of EBNA2, which has been shown to be regulated, in part, by the EBNA1-dependent enhancer activity of the origin of replication (OriP) [14].
  • DNA methylation does not control, however, Qp (a promoter for EBNA1 transcripts only) in lymphoblastoid cell lines (LCLs), although in vitro methylated Qp-reporter gene constructs are silenced [15].

Anatomical context of EBNA-1

  • This cell line allowed us to examine expression from the endogenous latency gene promoters in the context of an actual latent infection and the presence of other EBNA proteins, in particular EBNA-2, which is presumed to coregulate transcription with EBNA-3C [16].
  • CONCLUSION: Our results suggest uniform EBNA1 transcription levels in BL and that microarray profiling can reveal novel insights on quantitative EBV gene transcription and its impact on lymphocyte biology [17].
  • Murine cytotoxic T lymphocytes recognize an epitope in an EBNA-1 fragment, but fail to lyse EBNA-1-expressing mouse cells [4].
  • The observed EBNA-1 expression was restricted to a fraction (5%-30%) of tumor epithelial cells [18].
  • Characterization of the antigen(s) in RA synovium by the Western immunoblotting technique revealed a 62,000-molecular-weight (mol-wt) protein, in contrast to the 70,000-85,000-mol-wt EBNA-1 antigen found in EBV-transformed cells [19].

Associations of EBNA-1 with chemical compounds

  • In addition, plasmids carrying the gene for resistance to hygromycin B and the 30-bp family of repeats yielded 10 to 100 times more hygromycin B-resistant colonies than the vector lacking the 30-bp family of repeats in both EBV-genome-positive cells and cells that express EBNA-1 [20].
  • Moreover, anti-VCP antibodies immunoprecipitated, from the lysate of calcium ionophore-stimulated lymphoblastoid cell lines, an 80-kd band that was reactive with a monoclonal anti-EBNA-1 antibody and with anti-modified citrulline antibodies [21].
  • Two thymines occur at unique positions within EBNA-1 binding sites 1 and 4 at the DS and become sensitive to oxidation by permanganate when EBNA-1 binds, but mutation of each to the consensus base, adenine, actually improved the activity of each half of the DS slightly [22].
  • However, EBNA-1 protein levels showed no detectable change during the cell cycle, most likely due to the protein's long half-life as estimated by inhibition of protein synthesis by cycloheximide [23].
  • The MS patients had elevated IgG antibody to EBNA-1, as measured by reactivity with a synthetic glycine/alanine peptide, P62, which represents the glycine/alanine repeat in EBNA-1 [24].

Regulatory relationships of EBNA-1

  • Immunoblotting of LGL protein extracts established that, of the EBV gene products, EBV nuclear antigen-1 (EBNA-1) was expressed but EBNA-2 and the latent membrane protein (LMP-1) were not detectable in the leukemic cells [25].

Other interactions of EBNA-1

  • EBV RNA positivity was even higher in fresh samples stored at -80 degrees C until RNA expression analyses (88% for both EBNA1 and BARF1) [26].
  • Analysis of 12 nasopharyngeal carcinoma biopsies revealed significant levels of EBNA1 and LMP2A transcripts in almost every case but, in contrast to previous reports, LMP1 expression was undetectable [27].
  • When the new assays were used to screen a collection of endemic Burkitt's lymphoma tumours, abundant Qp-driven EBNA1 expression was found, whereas the other latent transcripts (with the exception of LMP2A) were either absent or detectable only at trace levels [27].
  • Immunoreactivities to these EBV proteins, BRRF2 and EBNA-1, were significantly higher in the serum and CSF of MS patients than in those of control donors [28].
  • Marked decreases in the levels of EBV nuclear antigen-1 (EBNA-1), EBNA-2, and EBNA-LP antibodies correlated with the increase in EBV-infected PBL [29].

Analytical, diagnostic and therapeutic context of EBNA-1


  1. Nuclear import of Epstein-Barr virus nuclear antigen 1 mediated by NPI-1 (Importin alpha5) is up- and down-regulated by phosphorylation of the nuclear localization signal for which Lys379 and Arg380 are essential. Kitamura, R., Sekimoto, T., Ito, S., Harada, S., Yamagata, H., Masai, H., Yoneda, Y., Yanagi, K. J. Virol. (2006) [Pubmed]
  2. Concomitant increase of LMP1 and CD25 (IL-2-receptor alpha) expression induced by IL-10 in the EBV-positive NK lines SNK6 and KAI3. Takahara, M., Kis, L.L., Nagy, N., Liu, A., Harabuchi, Y., Klein, G., Klein, E. Int. J. Cancer (2006) [Pubmed]
  3. Three restricted forms of Epstein-Barr virus latency counteracting apoptosis in c-myc-expressing Burkitt lymphoma cells. Kelly, G.L., Milner, A.E., Baldwin, G.S., Bell, A.I., Rickinson, A.B. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  4. Murine cytotoxic T lymphocytes recognize an epitope in an EBNA-1 fragment, but fail to lyse EBNA-1-expressing mouse cells. Mukherjee, S., Trivedi, P., Dorfman, D.M., Klein, G., Townsend, A. J. Exp. Med. (1998) [Pubmed]
  5. EBNA-1, the major nuclear antigen of Epstein-Barr virus, resembles 'RGG' RNA binding proteins. Snudden, D.K., Hearing, J., Smith, P.R., Grässer, F.A., Griffin, B.E. EMBO J. (1994) [Pubmed]
  6. Epstein-Barr virus nuclear antigen-1 and Myc cooperate in lymphomagenesis. Drotar, M.E., Silva, S., Barone, E., Campbell, D., Tsimbouri, P., Jurvansu, J., Bhatia, P., Klein, G., Wilson, J.B. Int. J. Cancer (2003) [Pubmed]
  7. Crystal structure of the DNA-binding domain of the Epstein-Barr virus origin-binding protein, EBNA1, bound to DNA. Bochkarev, A., Barwell, J.A., Pfuetzner, R.A., Bochkareva, E., Frappier, L., Edwards, A.M. Cell (1996) [Pubmed]
  8. Sequence-specific DNA binding of the Epstein-Barr virus nuclear antigen (EBNA-1) to clustered sites in the plasmid maintenance region. Rawlins, D.R., Milman, G., Hayward, S.D., Hayward, G.S. Cell (1985) [Pubmed]
  9. Epstein-Barr virus-associated Burkitt lymphomagenesis selects for downregulation of the nuclear antigen EBNA2. Kelly, G., Bell, A., Rickinson, A. Nat. Med. (2002) [Pubmed]
  10. Epstein-Barr virus nuclear protein EBNA3C is required for cell cycle progression and growth maintenance of lymphoblastoid cells. Maruo, S., Wu, Y., Ishikawa, S., Kanda, T., Iwakiri, D., Takada, K. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  11. Genetic evidence that EBNA-1 is needed for efficient, stable latent infection by Epstein-Barr virus. Lee, M.A., Diamond, M.E., Yates, J.L. J. Virol. (1999) [Pubmed]
  12. Construction and properties of an Epstein-Barr-virus-derived cDNA expression vector for human cells. Belt, P.B., Groeneveld, H., Teubel, W.J., van de Putte, P., Backendorf, C. Gene (1989) [Pubmed]
  13. Expression of the Epstein-Barr virus nuclear antigen-1 (EBNA-1) in the mouse can elicit the production of anti-dsDNA and anti-Sm antibodies. Sundar, K., Jacques, S., Gottlieb, P., Villars, R., Benito, M.E., Taylor, D.K., Spatz, L.A. J. Autoimmun. (2004) [Pubmed]
  14. Regulation of Epstein-Barr virus latency type by the chromatin boundary factor CTCF. Chau, C.M., Zhang, X.Y., McMahon, S.B., Lieberman, P.M. J. Virol. (2006) [Pubmed]
  15. Epigenotypes of latent herpesvirus genomes. Minarovits, J. Curr. Top. Microbiol. Immunol. (2006) [Pubmed]
  16. Epstein-Barr Virus EBNA-3C Is Targeted to and Regulates Expression from the Bidirectional LMP-1/2B Promoter. Jim??nez-Ram??rez, C., Brooks, A.J., Forshell, L.P., Yakimchuk, K., Zhao, B., Fulgham, T.Z., Sample, C.E. J. Virol. (2006) [Pubmed]
  17. Quantitative profiling of housekeeping and Epstein-Barr virus gene transcription in Burkitt lymphoma cell lines using an oligonucleotide microarray. Bernasconi, M., Berger, C., Sigrist, J.A., Bonanomi, A., Sobek, J., Niggli, F.K., Nadal, D. Virol. J. (2006) [Pubmed]
  18. Detection of Epstein-Barr virus in invasive breast cancers. Bonnet, M., Guinebretiere, J.M., Kremmer, E., Grunewald, V., Benhamou, E., Contesso, G., Joab, I. J. Natl. Cancer Inst. (1999) [Pubmed]
  19. Rheumatoid arthritis synovial membrane contains a 62,000-molecular-weight protein that shares an antigenic epitope with the Epstein-Barr virus-encoded associated nuclear antigen. Fox, R., Sportsman, R., Rhodes, G., Luka, J., Pearson, G., Vaughan, J. J. Clin. Invest. (1986) [Pubmed]
  20. trans activation of an Epstein-Barr viral transcriptional enhancer by the Epstein-Barr viral nuclear antigen 1. Reisman, D., Sugden, B. Mol. Cell. Biol. (1986) [Pubmed]
  21. Deiminated Epstein-Barr virus nuclear antigen 1 is a target of anti-citrullinated protein antibodies in rheumatoid arthritis. Pratesi, F., Tommasi, C., Anzilotti, C., Chimenti, D., Migliorini, P. Arthritis Rheum. (2006) [Pubmed]
  22. The minimal replicator of Epstein-Barr virus oriP. Yates, J.L., Camiolo, S.M., Bashaw, J.M. J. Virol. (2000) [Pubmed]
  23. Expression of EBNA-1 mRNA is regulated by cell cycle during Epstein-Barr virus type I latency. Davenport, M.G., Pagano, J.S. J. Virol. (1999) [Pubmed]
  24. An Epstein Barr virus-related cross reactive autoimmune response in multiple sclerosis in Norway. Vaughan, J.H., Riise, T., Rhodes, G.H., Nguyen, M.D., Barrett-Connor, E., Nyland, H. J. Neuroimmunol. (1996) [Pubmed]
  25. Epstein-Barr viral DNA in acute large granular lymphocyte (natural killer) leukemic cells. Hart, D.N., Baker, B.W., Inglis, M.J., Nimmo, J.C., Starling, G.C., Deacon, E., Rowe, M., Beard, M.E. Blood (1992) [Pubmed]
  26. Noninvasive diagnosis of nasopharyngeal carcinoma: nasopharyngeal brushings reveal high Epstein-Barr virus DNA load and carcinoma-specific viral BARF1 mRNA. Stevens, S.J., Verkuijlen, S.A., Hariwiyanto, B., Harijadi, n.u.l.l., Paramita, D.K., Fachiroh, J., Adham, M., Tan, I.B., Haryana, S.M., Middeldorp, J.M. Int. J. Cancer (2006) [Pubmed]
  27. Analysis of Epstein-Barr virus latent gene expression in endemic Burkitt's lymphoma and nasopharyngeal carcinoma tumour cells by using quantitative real-time PCR assays. Bell, A.I., Groves, K., Kelly, G.L., Croom-Carter, D., Hui, E., Chan, A.T., Rickinson, A.B. J. Gen. Virol. (2006) [Pubmed]
  28. Identification of Epstein-Barr virus proteins as putative targets of the immune response in multiple sclerosis. Cepok, S., Zhou, D., Srivastava, R., Nessler, S., Stei, S., Büssow, K., Sommer, N., Hemmer, B. J. Clin. Invest. (2005) [Pubmed]
  29. Increased levels of circulating Epstein-Barr virus (EBV)-infected lymphocytes and decreased EBV nuclear antigen antibody responses are associated with the development of posttransplant lymphoproliferative disease in solid-organ transplant recipients. Riddler, S.A., Breinig, M.C., McKnight, J.L. Blood (1994) [Pubmed]
  30. Surface plasmon resonance biosensor for direct detection of antibody against Epstein-Barr virus. Vaisocherov??, H., Mrkvov??, K., Piliarik, M., Jinoch, P., Steinbachov??, M., Homola, J. Biosensors & bioelectronics (2007) [Pubmed]
  31. Multiplex-nested RT-PCR to evaluate latent and lytic Epstein Barr virus gene expression. Bergallo, M., Costa, C., Baro, S., Musso, T., Balbo, L., Merlino, C., Cavallo, R. J. Biotechnol. (2007) [Pubmed]
  32. Infection of Epstein-Barr virus in Colorectal Cancer in Chinese. Song, L.B., Zhang, X., Zhang, C.Q., Zhang, Y., Pan, Z.Z., Liao, W.T., Li, M.Z., Zeng, M.S. Ai Zheng (2006) [Pubmed]
  33. EBV gene expression in an NPC-related tumour. Hitt, M.M., Allday, M.J., Hara, T., Karran, L., Jones, M.D., Busson, P., Tursz, T., Ernberg, I., Griffin, B.E. EMBO J. (1989) [Pubmed]
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