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Gene Review

EBNA-1  -  EBNA-1, QUK transcript

Human herpesvirus 4

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Disease relevance of EBNA-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 [1].
  • The EBNA-1 gene was identified as another diverged locus, although its variation is believed not to correlate with EBV type [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].
  • The carboxyl-terminal one-third of the Epstein-Barr virus nuclear antigen (EBNA-1) encoded by the BamHI restriction fragment K was synthesized in Escherichia coli by use of a high-expression plasmid [4].
  • EBNA-1 also regulates viral gene expression and is required for cell immortalization, suggesting that LANA performs similar functions in the context of HHV-8 infection [5].
 

High impact information on EBNA-1

  • In addition, they contain multiple copies of the EBV genome, express the viral nuclear antigen (EBNA) and, most importantly, proceed to undergo transformation when placed back in culture [6].
  • 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 [7].
  • Both rabbit monospecific antibodies and mouse monoclonal antibodies against 28-kDa EBNA gave nuclear immunofluorescence staining on Epstein-Barr virus (EBV)-infected lymphoblastoid cell lines and recognized the appropriate intact EBNA polypeptide bands on immunoblots [4].
  • Despite continuous antigen presence due to persistent EBV infection, half of the proliferating EBNA1-specific CD4(+) T cells belonged to the central-memory compartment (T(CM)) [8].
  • The remaining EBNA1-specific CD4(+) T cells displayed an effector-memory phenotype (T(EM)), of which a minority rapidly secreted IFN upon stimulation with EBNA1 [8].
 

Chemical compound and disease context of EBNA-1

 

Biological context of EBNA-1

  • 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 [11].
  • We hypothesized that transcription levels of EBNA1, the gene essential for EBV persistence within an infected cell, are similar in BL cell lines [12].
  • 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) [13].
  • In the Epstein-Barr virus genome, a total of 26 EBNA-1-binding sites occur within three clustered loci referred to as the family of repeats and dyad symmetry locus of ori-P and the separate BamHI-Q locus [14].
  • These reconstruction experiments demonstrated that a transactivation domain exists within the carboxy-terminal region of EBNA-1, that transactivation is more efficient when a nuclear localization signal is present, and that the natural karyophilic signal lies outside of the carboxy-terminal 191 amino acids [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 [12].
  • Presumably, initiation of replication at the DS, mediated by EBNA-1, is important for the natural life cycle of EBV, perhaps in establishing latent infections of normal B cells [17].
  • COS-1 cells will thus provide a valuable system in which to analyze functional domains of the EBNA gene [18].
  • In mouse fibroblast cell lines expressing PyV large T antigen (LT) and either BPV1 E2 or EBV EBNA1, the long-term episomal replication of plasmids carrying the PyV minimal origin together with the MME or family of repeats (FR) element can be monitored easily for 1 month under nonselective conditions [19].
 

Associations of EBNA-1 with chemical compounds

  • Similar results were obtained when a partially purified preparation of intact Raji EBNA-1 was substituted for the 28K EBNA-1, and the results were further supported by methylation interference studies which indicated contact points between EBNA-1 and the guanine residues at positions -8, -7, and +3 of the binding site [14].
  • EBNA-1 was then purified by applying the whole cell extract soluble fraction to a Ni-NTA Superflow column and eluting with an imidazole gradient [20].
  • EBNA-1 can subdue immune recognition by virtue of a long glycine and alanine-rich repeat, which interferes with the proteasomal degradation of EBNA-1 and in this way averts the presentation of antigenic peptides derived from it [21].
  • Thereafter, an alternative EBNA promoter, Cp, becomes dominant, Wp activity declines dramatically, and bisulfite sequencing of EBV-transformed lymphoblastoid cell lines (LCLs) shows extensive Wp methylation [22].
  • EBNA1 was also found to bind the arginine methyltransferases PRMT1 and PRMT5 [10].
 

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) [23].
  • 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 [24].
 

Analytical, diagnostic and therapeutic context of EBNA-1

References

  1. 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]
  2. The genome of Epstein-Barr virus type 2 strain AG876. Dolan, A., Addison, C., Gatherer, D., Davison, A.J., McGeoch, D.J. Virology (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. Carboxyl-terminal domain of the Epstein-Barr virus nuclear antigen is highly immunogenic in man. Milman, G., Scott, A.L., Cho, M.S., Hartman, S.C., Ades, D.K., Hayward, G.S., Ki, P.F., August, J.T., Hayward, S.D. Proc. Natl. Acad. Sci. U.S.A. (1985) [Pubmed]
  5. Carboxy terminus of human herpesvirus 8 latency-associated nuclear antigen mediates dimerization, transcriptional repression, and targeting to nuclear bodies. Schwam, D.R., Luciano, R.L., Mahajan, S.S., Wong, L., Wilson, A.C. J. Virol. (2000) [Pubmed]
  6. Early events in Epstein-Barr virus infection provide a model for B cell activation. Thorley-Lawson, D.A., Mann, K.P. J. Exp. Med. (1985) [Pubmed]
  7. 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]
  8. Distinct memory CD4+ T-cell subsets mediate immune recognition of Epstein Barr virus nuclear antigen 1 in healthy virus carriers. Heller, K.N., Upshaw, J., Seyoum, B., Zebroski, H., Münz, C. Blood (2007) [Pubmed]
  9. Epstein-barr virus-induced resistance to drugs that activate the mitotic spindle assembly checkpoint in Burkitt's lymphoma cells. Leao, M., Anderton, E., Wade, M., Meekings, K., Allday, M.J. J. Virol. (2007) [Pubmed]
  10. Regulation of the EBNA1 Epstein-Barr virus protein by serine phosphorylation and arginine methylation. Shire, K., Kapoor, P., Jiang, K., Hing, M.N., Sivachandran, N., Nguyen, T., Frappier, L. J. Virol. (2006) [Pubmed]
  11. Epigenotypes of latent herpesvirus genomes. Minarovits, J. Curr. Top. Microbiol. Immunol. (2006) [Pubmed]
  12. 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]
  13. 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]
  14. Definition of the sequence requirements for binding of the EBNA-1 protein to its palindromic target sites in Epstein-Barr virus DNA. Ambinder, R.F., Shah, W.A., Rawlins, D.R., Hayward, G.S., Hayward, S.D. J. Virol. (1990) [Pubmed]
  15. Functional domains of Epstein-Barr virus nuclear antigen EBNA-1. Ambinder, R.F., Mullen, M.A., Chang, Y.N., Hayward, G.S., Hayward, S.D. J. Virol. (1991) [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. Initiation of DNA replication within oriP is dispensable for stable replication of the latent Epstein-Barr virus chromosome after infection of established cell lines. Norio, P., Schildkraut, C.L., Yates, J.L. J. Virol. (2000) [Pubmed]
  18. Expression in COS-1 cells of Epstein-Barr virus nuclear antigen from a complete gene and a deleted gene. Robert, M.F., Shedd, D., Weigel, R.J., Fischer, D.K., Miller, G. J. Virol. (1984) [Pubmed]
  19. Episomal maintenance of plasmids with hybrid origins in mouse cells. Silla, T., Hääl, I., Geimanen, J., Janikson, K., Abroi, A., Ustav, E., Ustav, M. J. Virol. (2005) [Pubmed]
  20. Overproduction in Escherichia coli and purification of Epstein-Barr virus EBNA-1. Duellman, S.J., Burgess, R.R. Protein Expr. Purif. (2006) [Pubmed]
  21. In cis inhibition of antigen processing by the latency-associated nuclear antigen I of Kaposi sarcoma Herpes virus. Zaldumbide, A., Ossevoort, M., Wiertz, E.J., Hoeben, R.C. Mol. Immunol. (2007) [Pubmed]
  22. Methylation Status of theEpstein-Barr Virus (EBV) BamHI W Latent Cycle Promoter and Promoter Activity: Analysis with Novel EBV-Positive Burkitt and Lymphoblastoid Cell Lines. Hutchings, I.A., Tierney, R.J., Kelly, G.L., Stylianou, J., Rickinson, A.B., Bell, A.I. J. Virol. (2006) [Pubmed]
  23. 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]
  24. 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]
  25. 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]
  26. 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]
  27. 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]
  28. No direct role for Epstein-Barr virus in oral carcinogenesis: a study at the DNA, RNA and protein levels. Cruz, I., Van Den Brule, A.J., Brink, A.A., Snijders, P.J., Walboomers, J.M., Van Der Waal, I., Meijer, C.J. Int. J. Cancer (2000) [Pubmed]
 
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