Three Epstein-Barr virus latency proteins independently promote genomic instability by inducing DNA damage, inhibiting DNA repair and inactivating cell cycle checkpoints.
Epstein-Barr virus (EBV) has been implicated in the pathogenesis of human malignancies, but its contribution to tumorigenesis is not well understood. EBV carriage is associated with increased genomic instability in Burkitt's lymphoma, suggesting that viral products may induce this tumor phenotype. Using a panel of transfected sublines of the B-lymphoma line BJAB expressing the viral genes associated with latent infection, we show that the EBV nuclear antigens, EBNA-1 and EBNA-3C, and the latent membrane protein 1, LMP-1, independently promote genomic instability, as detected by nonclonal chromosomal aberrations, DNA breaks and phosphorylation of histone H2AX. EBNA-1 promotes the generation of DNA damage by inducing reactive oxygen species (ROS), whereas DNA repair is inhibited in LMP-1-expressing cells through downregulation of the DNA damage-sensing kinase, ataxia telangiectasia mutated (ATM), reduction of phosphorylation of its downstream targets Chk2 and inactivation of the G(2) checkpoint. EBNA-3C enhances the propagation of damaged DNA through inactivation of the mitotic spindle checkpoint and transcriptional downregulation of BubR1. Thus, multiple cellular functions involved in the maintenance of genome integrity seem to be independently targeted by EBV, pointing to the induction of genomic instability as a critical event in viral oncogenesis.
Gruhne
B
B
Department of Cell and Molecular Biology, Karolinska Institutet, S-171 77 Stockholm, Sweden.
Sompallae
R
R
Masucci
M G
MG
D000956:Antigens, Viral / Q000235:genetics*; D064007:Ataxia Telangiectasia Mutated Proteins; D002051:Burkitt Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000821:virology*; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D019309:Epstein-Barr Virus Nuclear Antigens / Q000235:genetics; D042822:Genomic Instability; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000502:physiology*; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D008941:Spindle Apparatus; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000235:genetics; D017735:Virus Latency
D000956:Antigens, Viral; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C498774:EBNA-3C, epstein-barr virus; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D019309:Epstein-Barr Virus Nuclear Antigens; D017382:Reactive Oxygen Species; D025521:Tumor Suppressor Proteins; D014763:Viral Matrix Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C584277:BUB1 protein, human; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases; C417029:EBV-encoded nuclear antigen 1