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.
Highlights
Epstein-Barr Virus (EBV) is a ubiquitous human herpesvirus that infects over 90% of the adult population worldwide [1, 2]
We provide biochemical and genetic evidence that polymorphisms in the EBNA1 DNA binding domain (DBD) contribute to the risk phenotype associated with EBV in www.impactjournals.com/oncotarget www.impactjournals.com/oncotarget endemic nasopharyngeal carcinoma (NPC)
EBNA1 genes derived from NPC tumors typically have 6-8 amino acid substitutions relative to B95-8 strain at non-random positions within the DBD
Summary
Epstein-Barr Virus (EBV) is a ubiquitous human herpesvirus that infects over 90% of the adult population worldwide [1, 2]. Variations in viral gene expression and genome copy number can be found in different cell and tumor types, suggesting that variable latency control contributes to viral pathogenesis and cancer [5]. More recent generation sequencing has revealed a diverse spectrum of genetic variations, including many polymorphisms in EBV coding genes expressed during latent infection and in human www.impactjournals.com/oncotarget tumors [12]. EBNA1 is the viral encoded DNA binding protein essential for the stable maintenance of the EBV circular genome (referred to as episome) during latent infection [15, 16]. We show that V-val EBNA1 fails to support episome maintenance and suppress lytic cycle gene expression We propose that these biochemical and functional changes provide a mechanistic explanation for the cancer-risk associated with genetic variants of EBNA1
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