title: Carcinoma-risk variant of EBNA1 deregulates Epstein-Barr Virus episomal latency.
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.affiliation: The Wistar Institute, Philadelphia, PA USA.
authors.forename: Jayaraju
authors.initials: J
authors.lastname: Dheekollu
authors.affiliation: The Wistar Institute, Philadelphia, PA USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Malecka
authors.affiliation: The Wistar Institute, Philadelphia, PA USA.
authors.forename: Andreas
authors.initials: A
authors.lastname: Wiedmer
authors.affiliation: Deutsches Krebsforschungszentrum, Heidelberg, Germany.
authors.forename: Henri-Jacques
authors.initials: HJ
authors.lastname: Delecluse
authors.affiliation: Department of Pediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Alan K S
authors.initials: AK
authors.lastname: Chiang
authors.affiliation: The Wistar Institute, Philadelphia, PA USA.
authors.forename: Dario C
authors.initials: DC
authors.lastname: Altieri
authors.affiliation: The Wistar Institute, Philadelphia, PA USA.
authors.forename: Troy E
authors.initials: TE
authors.lastname: Messick
authors.affiliation: The Wistar Institute, Philadelphia, PA USA.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Lieberman
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology / Q000821:virology; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D002472:Cell Transformation, Viral; D018360:Crystallography, X-Ray; D004261:DNA Replication; D004279:DNA, Viral / Q000096:biosynthesis / Q000235:genetics*; D020031:Epstein-Barr Virus Infections / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D019309:Epstein-Barr Virus Nuclear Antigens / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006367:HeLa Cells; D004854:Herpesvirus 4, Human / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism / Q000472:pathogenicity; D054884:Host-Pathogen Interactions; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D010957:Plasmids; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D000077022:Survivin; D017735:Virus Latency; D014779:Virus Replication
chemical_list: C107489:BIRC5 protein, human; D004279:DNA, Viral; D019309:Epstein-Barr Virus Nuclear Antigens; D051034:Inhibitor of Apoptosis Proteins; D000077022:Survivin; C417029:EBV-encoded nuclear antigen 1
keywords: EBNA1; epstein-barr virus (EBV); latency; nasopharyngeal carcinoma (NPC); survivin