Hepatitis C virus inhibits DNA damage repair through reactive oxygen and nitrogen species and by interfering with the ATM-NBS1/Mre11/Rad50 DNA repair pathway in monocytes and hepatocytes.
Hepatitis C virus (HCV) infection is associated with the development of hepatocellular carcinoma and putatively also non-Hodgkin's B cell lymphoma. In this study, we demonstrated that PBMCs obtained from HCV-infected patients showed frequent chromosomal aberrations and that HCV infection of B cells in vitro induced enhanced chromosomal breaks and sister chromatid exchanges. HCV infection hypersensitized cells to ionizing radiation and bleomycin and inhibited nonhomologous end-joining repair. The viral core and nonstructural protein 3 proteins were shown to be responsible for the inhibition of DNA repair, mediated by NO and reactive oxygen species. Stable expression of core protein induced frequent chromosome translocations in cultured cells and in transgenic mice. HCV core protein binds to the NBS1 protein and inhibits the formation of the Mre11/NBS1/Rad50 complex, thereby affecting ATM activation and inhibiting DNA binding of repair enzymes. Taken together, these data indicate that HCV infection inhibits multiple DNA repair processes to potentiate chromosome instability in both monocytes and hepatocytes. These effects may explain the oncogenicity and immunological perturbation of HCV infection.
Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. kmachida@usc.edu
Keigo
K
Machida
George
G
McNamara
Kevin T-H
KT
Cheng
Jeffrey
J
Huang
Chun-Hsiang
CH
Wang
Lucio
L
Comai
Jing-Hsiung James
JH
Ou
Michael M C
MM
Lai
D017766:Acid Anhydride Hydrolases; D000818:Animals; D001260:Ataxia Telangiectasia / Q000201:enzymology; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004249:DNA Damage / Q000276:immunology*; D004260:DNA Repair / Q000276:immunology*; D045643:DNA Repair Enzymes / Q000037:antagonists & inhibitors / Q000502:physiology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D057809:HEK293 Cells; D056945:Hep G2 Cells; D016174:Hepacivirus / Q000276:immunology*; D022781:Hepatocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D006801:Humans; D000076228:MRE11 Homologue Protein; D051379:Mice; D008822:Mice, Transgenic; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D026361:Reactive Nitrogen Species / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000494:pharmacology*; D015398:Signal Transduction / Q000276:immunology; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014758:Viral Core Proteins / Q000378:metabolism
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; C112156:NBN protein, human; C508551:NHEJ1 protein, human; D009687:Nuclear Proteins; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D025521:Tumor Suppressor Proteins; D014758:Viral Core Proteins; C069130:nucleocapsid protein, Hepatitis C virus; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D000076228:MRE11 Homologue Protein; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D045643:DNA Repair Enzymes