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Carcinoma-risk variant of EBNA1 deregulates Epstein-Barr Virus episomal latency.
Oncotarget. 2017 Jan 31; 8(5):7248-7264.O

Abstract

Epstein-Barr Virus (EBV) latent infection is a causative co-factor for endemic Nasopharyngeal Carcinoma (NPC). NPC-associated variants have been identified in EBV-encoded nuclear antigen EBNA1. Here, we solve the X-ray crystal structure of an NPC-derived EBNA1 DNA binding domain (DBD) and show that variant amino acids are found on the surface away from the DNA binding interface. We show that NPC-derived EBNA1 is compromised for DNA replication and episome maintenance functions. Recombinant virus containing the NPC EBNA1 DBD are impaired in their ability to immortalize primary B-lymphocytes and suppress lytic transcription during early stages of B-cell infection. We identify Survivin as a host protein deficiently bound by the NPC variant of EBNA1 and show that Survivin depletion compromises EBV episome maintenance in multiple cell types. We propose that endemic variants of EBNA1 play a significant role in EBV-driven carcinogenesis by altering key regulatory interactions that destabilize latent infection.

Authors+Show Affiliations

The Wistar Institute, Philadelphia, PA USA.The Wistar Institute, Philadelphia, PA USA.The Wistar Institute, Philadelphia, PA USA.Deutsches Krebsforschungszentrum, Heidelberg, Germany.Department of Pediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong.The Wistar Institute, Philadelphia, PA USA.The Wistar Institute, Philadelphia, PA USA.The Wistar Institute, Philadelphia, PA USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28077791

Citation

Dheekollu, Jayaraju, et al. "Carcinoma-risk Variant of EBNA1 Deregulates Epstein-Barr Virus Episomal Latency." Oncotarget, vol. 8, no. 5, 2017, pp. 7248-7264.
Dheekollu J, Malecka K, Wiedmer A, et al. Carcinoma-risk variant of EBNA1 deregulates Epstein-Barr Virus episomal latency. Oncotarget. 2017;8(5):7248-7264.
Dheekollu, J., Malecka, K., Wiedmer, A., Delecluse, H. J., Chiang, A. K., Altieri, D. C., Messick, T. E., & Lieberman, P. M. (2017). Carcinoma-risk variant of EBNA1 deregulates Epstein-Barr Virus episomal latency. Oncotarget, 8(5), 7248-7264. https://doi.org/10.18632/oncotarget.14540
Dheekollu J, et al. Carcinoma-risk Variant of EBNA1 Deregulates Epstein-Barr Virus Episomal Latency. Oncotarget. 2017 Jan 31;8(5):7248-7264. PubMed PMID: 28077791.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Carcinoma-risk variant of EBNA1 deregulates Epstein-Barr Virus episomal latency. AU - Dheekollu,Jayaraju, AU - Malecka,Kimberly, AU - Wiedmer,Andreas, AU - Delecluse,Henri-Jacques, AU - Chiang,Alan K S, AU - Altieri,Dario C, AU - Messick,Troy E, AU - Lieberman,Paul M, PY - 2016/10/29/received PY - 2016/12/26/accepted PY - 2017/1/13/pubmed PY - 2018/3/3/medline PY - 2017/1/13/entrez KW - EBNA1 KW - epstein-barr virus (EBV) KW - latency KW - nasopharyngeal carcinoma (NPC) KW - survivin SP - 7248 EP - 7264 JF - Oncotarget JO - Oncotarget VL - 8 IS - 5 N2 - Epstein-Barr Virus (EBV) latent infection is a causative co-factor for endemic Nasopharyngeal Carcinoma (NPC). NPC-associated variants have been identified in EBV-encoded nuclear antigen EBNA1. Here, we solve the X-ray crystal structure of an NPC-derived EBNA1 DNA binding domain (DBD) and show that variant amino acids are found on the surface away from the DNA binding interface. We show that NPC-derived EBNA1 is compromised for DNA replication and episome maintenance functions. Recombinant virus containing the NPC EBNA1 DBD are impaired in their ability to immortalize primary B-lymphocytes and suppress lytic transcription during early stages of B-cell infection. We identify Survivin as a host protein deficiently bound by the NPC variant of EBNA1 and show that Survivin depletion compromises EBV episome maintenance in multiple cell types. We propose that endemic variants of EBNA1 play a significant role in EBV-driven carcinogenesis by altering key regulatory interactions that destabilize latent infection. SN - 1949-2553 UR - https://www.unboundmedicine.com/medline/citation/28077791/Carcinoma_risk_variant_of_EBNA1_deregulates_Epstein_Barr_Virus_episomal_latency_ L2 - https://www.oncotarget.com/lookup/doi/10.18632/oncotarget.14540 DB - PRIME DP - Unbound Medicine ER -