Hepatitis C virus NS3/4A protein interacts with ATM, impairs DNA repair and enhances sensitivity to ionizing radiation

• Published in: Virology (New York, N.Y.) N.Y.), 2008-01, Vol.370 (2), p.295-309
• Main Authors: Lai, Chao-Kuen, Jeng, King-Song, Machida, Keigo, Cheng, Yi-Sheng, Lai, Michael M.C
• Format: Article
• Language: English
• Subjects: Ataxia Telangiectasia Mutated Proteins; Ataxia-telangiectasia mutated; Binding Sites; Carrier Proteins - genetics; Carrier Proteins - physiology; Cell Cycle Proteins - chemistry; Cell Cycle Proteins - genetics; Cell Cycle Proteins - physiology; Cell Line; Cytoplasm - metabolism; DNA; DNA DAMAGES; DNA REPAIR; DNA Repair - physiology; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - genetics; DNA-Binding Proteins - physiology; Double-strand DNA breaks; HeLa Cells; Hepacivirus - genetics; Hepacivirus - pathogenicity; Hepacivirus - physiology; HEPATITIS; Hepatitis C virus; HEPATOMAS; Humans; Infectious Disease; IONIZING RADIATIONS; IRRADIATION; LYMPHOMAS; Nonstructural protein NS3/4A; NUCLEOSIDES; Oncogenesis; Phosphorylation; Protein-Serine-Threonine Kinases - chemistry; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - physiology; PROTEINS; Radiation Tolerance - physiology; RADIATION, THERMAL, AND OTHER ENVIRONMENTAL POLLUTANT EFFECTS ON LIVING ORGANISMS AND BIOLOGICAL MATERIALS; RADIOSENSITIVITY; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Replicon; SERINE; Tumor Suppressor Proteins - chemistry; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - physiology; Viral Nonstructural Proteins - genetics; Viral Nonstructural Proteins - physiology; Viral Proteins - genetics; Viral Proteins - physiology; VIRUSES; γ-H2AX foci
• ISSN: 0042-6822; 1096-0341
• DOI: 10.1016/j.virol.2007.08.037

Abstract Hepatitis C virus (HCV) infection is frequently associated with the development of hepatocellular carcinomas and non-Hodgkin's B-cell lymphomas. Nonstructural protein 3 (NS3) of HCV possesses serine protease, nucleoside triphosphatase, and helicase activities, while NS4A functions as a cofactor for the NS3 serine protease. Here, we show that HCV NS3/4A interacts with the ATM (ataxia-telangiectasia mutated), a cellular protein essential for cellular response to irradiation. The expression of NS3/4A caused cytoplasmic translocation of either endogenous or exogenous ATM and delayed dephosphorylation of the phosphorylated ATM and γ-H2AX following ionizing irradiation. As a result, the irradiation-induced γ-H2AX foci persisted longer in the NS3/4A-expressing cells. Furthermore, these cells showed increased comet tail moment in single-cell electrophoresis assay, indicating increased double-strand DNA breaks. The cells harboring an HCV replicon also exhibited cytoplasmic localization of ATM and increased sensitivity to irradiation. These results demonstrate that NS3/4A impairs the efficiency of DNA repair by interacting with ATM and renders the cells more sensitive to DNA damage. This effect may contribute to HCV oncogenesis.