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.
Keywords:
EBNA1; epstein-barr virus (EBV); latency; nasopharyngeal carcinoma (NPC); survivin.
MeSH terms
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B-Lymphocytes / metabolism
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B-Lymphocytes / pathology
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B-Lymphocytes / virology
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Carcinoma / metabolism
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Carcinoma / pathology
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Carcinoma / virology*
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Cell Transformation, Viral*
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Crystallography, X-Ray
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DNA Replication
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DNA, Viral / biosynthesis
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DNA, Viral / genetics*
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Epstein-Barr Virus Infections / metabolism
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Epstein-Barr Virus Infections / pathology
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Epstein-Barr Virus Infections / virology*
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Epstein-Barr Virus Nuclear Antigens / chemistry
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Epstein-Barr Virus Nuclear Antigens / genetics*
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Epstein-Barr Virus Nuclear Antigens / metabolism
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HeLa Cells
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Herpesvirus 4, Human / genetics*
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Herpesvirus 4, Human / growth & development
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Herpesvirus 4, Human / metabolism
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Herpesvirus 4, Human / pathogenicity
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Host-Pathogen Interactions
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Humans
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Inhibitor of Apoptosis Proteins / genetics
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Inhibitor of Apoptosis Proteins / metabolism
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Models, Molecular
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Nasopharyngeal Carcinoma
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Nasopharyngeal Neoplasms / metabolism
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Nasopharyngeal Neoplasms / pathology
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Nasopharyngeal Neoplasms / virology*
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Plasmids
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Protein Binding
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Protein Interaction Domains and Motifs
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Survivin
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Virus Latency*
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Virus Replication
Substances
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BIRC5 protein, human
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DNA, Viral
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Epstein-Barr Virus Nuclear Antigens
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Inhibitor of Apoptosis Proteins
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Survivin
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EBV-encoded nuclear antigen 1