Epstein–Barr virus nuclear antigen 1

EBNA1 is integral to many EBV functions including gene regulation, extrachromosomal replication, and maintenance of the EBV episomal genome through positive and negative regulation of viral promoters. Studies show that the phosphorylation of ten specific sites on EBNA1 regulates these functions. When phosphorylation does not occur, replication and transcription activities of the protein are significantly decreased. EBNA1 binds to sequence-specific sites at the origin of viral replication (oriP) within the viral episome. The oriP has four EBNA1 binding sites (called the Dyad Symmetry; DS) where replication is initiated as well as a 20-site repeat segment (called the Family of Repeats; FR). EBNA1's specific binding ability, as well as its ability to tether EBV DNA to chromosomal DNA,{{Cite journal|author1=Nanbo, Asuka |author2=Arthur Sugden |author3=Bill Sugden |title= The coupling of synthesis and partitioning of EBV's plasmid replicon is revealed in live cells |journal= The EMBO Journal|volume=26 |issue=19|pages=4252–4262 |year=2007 |doi=10.1038/sj.emboj.7601853|pmid=17853891 |pmc=2000340 }} allows EBNA1 to mediate replication and partitioning of the episome during division of the host cell. EBNA1 also interacts with some viral promoters via several mechanisms,{{Cite journal |doi= 10.1128/MCB.23.19.6901-6908.2003 |author=Kennedy, Gregory |author2=Bill Sugden |title=EBNA1, a Bifunctional Transcription Activator |journal=Molecular and Cellular Biology |volume=23 |issue=19 |pages=6901–6908 |year=2003 |pmid= 12972608 |pmc=193932}} further contributing to transcriptional regulation of EBNA1 itself as well as the other EBNAs (2 and 3) and of EBV latent membrane protein 1 (LMP1).

Though EBNA1 is a well-characterized protein, its role in oncogenesis is less well defined. It is consistently expressed in EBV-associated tumors. EBNA1 is the only identified latent protein-encoding genes that it consistently expressed in Burkitt's lymphoma cells and is believed to contribute to EBV malignancies through B cell-directed expression. This expression has the ability to produce B-cell lymphomas in transgenic mice and contribute to the survival of Burkitt's lymphoma in vitro. EBNA1 may regulate cellular genes during EBV's latency phase and thus regulate EBV associated tumors. Some studies suggest that it is possible that EBNA1 may be involved in the maintenance function in tumors.{{Cite journal |author=Young, Lawrence S. |author2=Paul G. Murry |title= Epstein–Barr Virus and oncogenesis: from latent genes to tumors|journal= Oncogene |volume=22|issue= 33 |pages=5108–5121|year=2003|pmid= 12910248| doi=10.1038/sj.onc.1206556|doi-access=free}} Transgenic mice expressing EBNA1 in B cell lines showed a predisposition for developing B cell lymphoma, thus demonstrating that EBNA1 is a viral oncogene and that it likely plays a role in B cell neoplasia.{{Cite journal|author1=Wilson, J.B. |author2=J.L. Bell |author3=A.J. Levine |title= Expression of Epstein–Barr virus nuclear antigen-1 induces B cell neoplasia in transgenic mice |journal= The EMBO Journal|volume=15 |issue=12|pages=3117–3126|year=1996|pmc= 450254 |pmid=8670812|doi=10.1002/j.1460-2075.1996.tb00674.x }} Data also show that, though its role in extrachromosomal replication, EBNA1 also increases the growth of B cells,{{Cite journal|author= Humme, Siblille |title= The EBV nuclear antigen 1 (EBNA1) enhances B cell immortalization several thousandfold |journal= PNAS |volume=100 |issue=19 |pages=10989–10994|year=2003 |doi= 10.1073/pnas.1832776100|pmid= 12947043|pmc= 196914|bibcode= 2003PNAS..10010989H |display-authors=etal|doi-access= free }} thus aiding in the formation of malignancies. Adoptive ex vivo transfer of EBNA-1-specific T cells is a feasible and well-tolerated therapeutic option,{{cite journal |vauthors=Icheva V, Kayser S, Wolff D, Tuve S, Kyzirakos C, Bethge W, Greil J, Albert MH, Schwinger W, Nathrath M, Schumm M, Stevanovic S, Handgretinger R, Lang P, Feuchtinger T |title=Adoptive transfer of epstein-barr virus (EBV) nuclear antigen 1-specific t cells as treatment for EBV reactivation and lymphoproliferative disorders after allogeneic stem-cell transplantation |journal=J Clin Oncol |date=Jan 2013 |volume=31 |issue=1 |pages=39–48 |doi=10.1200/JCO.2011.39.8495 |pmid=23169501|doi-access=free }} however for optimal efficacy expansion protocols should use antigenic sequences from relevant EBV strains.{{cite journal|last=Jones|first=K|author2=Nourse JP |author3=Morrison L |author4=Nguyen-Van D |author5=Moss DJ |author6=Burrows SR |author7=Gandhi MK. |title=Expansion of EBNA1-specific effector T cells in posttransplantation lymphoproliferative disorders|journal=Blood|date=Sep 2010|volume=116|issue=13|pages=2245–52|doi=10.1182/blood-2010-03-274076|pmid=20562330|doi-access=free}}

EBNA1 has been linked to the epithelial to mesenchymal transition (EMT) in nasopharyngeal carcinoma cells.{{cite journal|last=Wang|first=Lu |author2=Tian, Wen-Dong |author3=Xu, Xia |author4=Nie, Biao |author5=Lu, Juan |author6=Liu, Xiong |author7=Zhang, Bao |author8=Dong, Qi |author9=Sunwoo, John B. |author10=Li, Gang |author11=Li, Xiang-Ping |title=Epstein-Barr virus nuclear antigen 1 (EBNA1) protein induction of epithelial-mesenchymal transition in nasopharyngeal carcinoma cells |journal=Cancer |date=1 February 2014 |volume=120 |issue=3 |pages=363–372 |doi=10.1002/cncr.28418 |pmid=24190575|doi-access=free }} The link has been associated with the TGF-β1/miR-200/ZEB pathway.

• Epstein–Barr virus nuclear-antigen internal ribosomal entry site

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{{Viral proteins}}

{{DEFAULTSORT:Epstein-Barr Nuclear Antigen 1}}

Category:Viral nonstructural proteins

Category:Epstein–Barr virus