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Gene Review

BMRF1  -  early antigen protein D

Human herpesvirus 4

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Disease relevance of BMRF1


High impact information on BMRF1

  • Here we demonstrate that the retinoic acid receptor alpha (RAR alpha) and retinoid X receptor alpha (RXR alpha) inhibit the ability of the Z protein to transactivate the viral early promoter BMRF1, which directs transcription of EA-D [5].
  • RXR alpha inhibits Z from binding to the AP-1 motif in the BMRF1 promoter and, reciprocally, Z inhibits RAR alpha from binding to its retinoic acid response element in the BRE promoter [5].
  • Transactivation efficiency of the EBV BMRF1 promoter by Z is cell type dependent [6].
  • In B cells, in which EBV typically exists in a latent form, Z activates the BMRF1 promoter inefficiently [6].
  • Bromodeoxyuridine-labeled chromatin immunodepletion analyses confirmed that PCNA is loaded onto newly synthesized viral DNA as well as BALF2 and BMRF1 viral proteins during lytic replication [7].

Chemical compound and disease context of BMRF1


Biological context of BMRF1

  • Furthermore, the anti-PCNA, -MSH2, -MSH3, or -MSH6 antibodies could immunoprecipitate BMRF1 replication protein probably via the viral DNA genome [7].
  • Despite the presence of an R binding site, the BMRF1 promoter is only moderately responsive to R alone in either HeLa or Jurkat cells [12].
  • These observations strongly suggest that the presence of EBV DNA polymerase accessory protein, BMRF1 gene product, does influence the enzymatic properties of EBV DNA polymerase catalytic subunit [13].
  • This same family of polypeptides was identified when the immunoblots were reacted with the R3 monoclonal antibody, and we concluded that this antibody also recognized the product of the BMRF1 open reading frame [14].
  • In one orientation, termed BamHI-M rightward reading frame 1 (BMRF1), a set of phosphoproteins ranging in size from 47,000 to 54,000 daltons was synthesized [15].

Anatomical context of BMRF1


Associations of BMRF1 with chemical compounds

  • The addition of the BMRF1 polymerase accessory subunit to the reaction enhanced the double-strand exonucleolytic activity in the presence of high concentrations of ammonium sulfate (fourfold stimulation at 75 mM ammonium sulfate) [17].
  • Glutathione S-transferase-Mta bound to BMRF1 and BMLF1 transcripts but not to a control cellular gene RNA [18].
  • Inhibition of viral DNA replication with phosphonoacetic acid, a viral DNA Pol inhibitor, eliminated the DNA-bound form of the BMRF1 protein, although the protein was sufficiently expressed in the cells [19].
  • 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 [20].

Physical interactions of BMRF1

  • These observations suggest that the BMRF1 polymerase accessory subunit forms a complex with the BALF5 polymerase catalytic subunit to stabilize the interaction of the holoenzyme complex with the 3'-OH end of the primer on the template DNA during exonucleolysis [17].

Regulatory relationships of BMRF1

  • In contrast, BZLF1-induced activation of the BMRF1 promoter is inhibited in the presence of the BMRF1 gene product [21].
  • The BMRF2 promoter may be regulated differentially from the BMRF1 promoter and more closely resembles that of BDLF3 [22].
  • We demonstrate that a region of oriLyt (the "downstream component"), previously shown to be one of two domains absolutely essential for oriLyt replication, is required for BMRF1-induced activation of the BHLF1 promoter [23].

Other interactions of BMRF1

  • Sequence analysis revealed that this clone contains about 75% of the BMRF1 and the complete BMRF2 open reading frames [24].
  • Additionally, it was demonstrated that BGLF4 co-localizes with viral DNA polymerase processivity factor, EA-D (BMRF1), in the virus replication compartment and that it is a virion component [25].
  • Optimal stimulation was obtained when the molar ratio of BMRF1 protein to BALF5 protein was 2 and higher, identical to the values required for reconstituting the optimum DNA polymerizing activity (T. Tsurumi, T. Daikoku, R. Kurachi, and Y. Nishiyama, J. Virol. 67:7648-7653, 1993) [17].
  • Each of the replication-negative Zta variants was capable of transactivating expression from both BHLF1 promoter-chloramphenicol acetyltransferase constructions and the BMRF1 promoter on endogenous EBV genomes in Raji cells with efficiency comparable to that of the wild-type polypeptide [26].
  • 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 [27].

Analytical, diagnostic and therapeutic context of BMRF1


  1. Functional role of phosphatidylinositol 3-kinase/Akt pathway on cell growth and lytic cycle of Epstein-Barr virus in the Burkitt's lymphoma cell line, P3HR-1. Mori, T., Sairenji, T. Virus Genes (2006) [Pubmed]
  2. Lytic induction and apoptosis of Epstein-Barr virus-associated gastric cancer cell line with epigenetic modifiers and ganciclovir. Jung, E.J., Lee, Y.M., Lee, B.L., Chang, M.S., Kim, W.H. Cancer Lett. (2007) [Pubmed]
  3. The Epstein-Barr virus polymerase accessory factor BMRF1 adopts a ring-shaped structure as visualized by electron microscopy. Makhov, A.M., Subramanian, D., Holley-Guthrie, E., Kenney, S.C., Griffith, J.D. J. Biol. Chem. (2004) [Pubmed]
  4. Purification and characterization of the DNA-binding activity of the Epstein-Barr virus DNA polymerase accessory protein BMRF1 gene products, as expressed in insect cells by using the baculovirus system. Tsurumi, T. J. Virol. (1993) [Pubmed]
  5. Retinoic acid is a negative regulator of the Epstein-Barr virus protein (BZLF1) that mediates disruption of latent infection. Sista, N.D., Pagano, J.S., Liao, W., Kenney, S. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  6. The bZIP transactivator of Epstein-Barr virus, BZLF1, functionally and physically interacts with the p65 subunit of NF-kappa B. Gutsch, D.E., Holley-Guthrie, E.A., Zhang, Q., Stein, B., Blanar, M.A., Baldwin, A.S., Kenney, S.C. Mol. Cell. Biol. (1994) [Pubmed]
  7. Postreplicative mismatch repair factors are recruited to epstein-barr virus replication compartments. Daikoku, T., Kudoh, A., Sugaya, Y., Iwahori, S., Shirata, N., Isomura, H., Tsurumi, T. J. Biol. Chem. (2006) [Pubmed]
  8. Ganciclovir augments the lytic induction and apoptosis induced by chemotherapeutic agents in an Epstein-Barr virus-infected gastric carcinoma cell line. Ji Jung, E., Mie Lee, Y., Lan Lee, B., Soo Chang, M., Ho Kim, W. Anticancer Drugs (2007) [Pubmed]
  9. Bipartite DNA-binding region of the Epstein-Barr virus BMRF1 product essential for DNA polymerase accessory function. Kiehl, A., Dorsky, D.I. J. Virol. (1995) [Pubmed]
  10. Fatty acid synthase expression is induced by the Epstein-Barr virus immediate-early protein BRLF1 and is required for lytic viral gene expression. Li, Y., Webster-Cyriaque, J., Tomlinson, C.C., Yohe, M., Kenney, S. J. Virol. (2004) [Pubmed]
  11. Expression of an early Epstein-Barr virus antigen (EA-D) in E. coli. Brief report. Roeckel, D., Boos, H., Mueller-Lantzsch, N. Arch. Virol. (1987) [Pubmed]
  12. Direct BRLF1 binding is required for cooperative BZLF1/BRLF1 activation of the Epstein-Barr virus early promoter, BMRF1. Quinlivan, E.B., Holley-Guthrie, E.A., Norris, M., Gutsch, D., Bachenheimer, S.L., Kenney, S.C. Nucleic Acids Res. (1993) [Pubmed]
  13. Functional expression and characterization of the Epstein-Barr virus DNA polymerase catalytic subunit. Tsurumi, T., Kobayashi, A., Tamai, K., Daikoku, T., Kurachi, R., Nishiyama, Y. J. Virol. (1993) [Pubmed]
  14. A second Epstein-Barr virus early antigen gene in BamHI fragment M encodes a 48- to 50-kilodalton nuclear protein. Cho, M.S., Milman, G., Hayward, S.D. J. Virol. (1985) [Pubmed]
  15. Identification and mapping of Epstein-Barr virus early antigens and demonstration of a viral gene activator that functions in trans. Wong, K.M., Levine, A.J. J. Virol. (1986) [Pubmed]
  16. The Epstein-Barr virus protein BMRF1 activates gastrin transcription. Holley-Guthrie, E.A., Seaman, W.T., Bhende, P., Merchant, J.L., Kenney, S.C. J. Virol. (2005) [Pubmed]
  17. Further characterization of the interaction between the Epstein-Barr virus DNA polymerase catalytic subunit and its accessory subunit with regard to the 3'-to-5' exonucleolytic activity and stability of initiation complex at primer terminus. Tsurumi, T., Daikoku, T., Nishiyama, Y. J. Virol. (1994) [Pubmed]
  18. Mta has properties of an RNA export protein and increases cytoplasmic accumulation of Epstein-Barr virus replication gene mRNA. Semmes, O.J., Chen, L., Sarisky, R.T., Gao, Z., Zhong, L., Hayward, S.D. J. Virol. (1998) [Pubmed]
  19. Architecture of replication compartments formed during Epstein-Barr virus lytic replication. Daikoku, T., Kudoh, A., Fujita, M., Sugaya, Y., Isomura, H., Shirata, N., Tsurumi, T. J. Virol. (2005) [Pubmed]
  20. The bZip dimerization domain of the Epstein-Barr virus BZLF1 (Z) protein mediates lymphoid-specific negative regulation. Hong, Y., Holley-Guthrie, E., Kenney, S. Virology (1997) [Pubmed]
  21. Functional and physical interactions between the Epstein-Barr virus (EBV) proteins BZLF1 and BMRF1: Effects on EBV transcription and lytic replication. Zhang, Q., Hong, Y., Dorsky, D., Holley-Guthrie, E., Zalani, S., Elshiekh, N.A., Kiehl, A., Le, T., Kenney, S. J. Virol. (1996) [Pubmed]
  22. Regulation of Epstein-Barr virus promoters in oral epithelial cells and lymphocytes. Lagenaur, L.A., Palefsky, J.M. J. Virol. (1999) [Pubmed]
  23. The Epstein-Barr virus (EBV) DNA polymerase accessory protein, BMRF1, activates the essential downstream component of the EBV oriLyt. Zhang, Q., Holley-Guthrie, E., Ge, J.Q., Dorsky, D., Kenney, S. Virology (1997) [Pubmed]
  24. Characterization of a cDNA clone corresponding to a transcript from the Epstein-Barr virus BamHI M fragment: evidence for overlapping mRNAs. Pfitzner, A.J., Strominger, J.L., Speck, S.H. J. Virol. (1987) [Pubmed]
  25. Detection of Epstein-Barr virus BGLF4 protein kinase in virus replication compartments and virus particles. Wang, J.T., Yang, P.W., Lee, C.P., Han, C.H., Tsai, C.H., Chen, M.R. J. Gen. Virol. (2005) [Pubmed]
  26. A replication function associated with the activation domain of the Epstein-Barr virus Zta transactivator. Sarisky, R.T., Gao, Z., Lieberman, P.M., Fixman, E.D., Hayward, G.S., Hayward, S.D. J. Virol. (1996) [Pubmed]
  27. Role of the epstein-barr virus RTA protein in activation of distinct classes of viral lytic cycle genes. Ragoczy, T., Miller, G. J. Virol. (1999) [Pubmed]
  28. Lytic viral replication as a contributor to the detection of Epstein-Barr virus in breast cancer. Huang, J., Chen, H., Hutt-Fletcher, L., Ambinder, R.F., Hayward, S.D. J. Virol. (2003) [Pubmed]
  29. Identification of transactivator and nuclear localization domains in the Epstein-Barr virus DNA polymerase accessory protein, BMRF1. Zhang, Q., Holley-Guthrie, E., Dorsky, D., Kenney, S. J. Gen. Virol. (1999) [Pubmed]
  30. ELISA for the detection of serum and saliva IgA against the BMRFI gene product of Epstein-Barr virus. Nadala, E.C., Tan, T.M., Wong, H.M., Ting, R.C. J. Med. Virol. (1996) [Pubmed]
  31. Real-time PCR measures Epstein-Barr Virus DNA in archival breast adenocarcinomas. Thorne, L.B., Ryan, J.L., Elmore, S.H., Glaser, S.L., Gulley, M.L. Diagn. Mol. Pathol. (2005) [Pubmed]
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