Hepatitis C virus NS3/4A protein interacts with ATM, impairs DNA repair and enhances sensitivity to ionizing radiation
- Institute of Molecular Biology, Academia Sinica, Taipei, 115, Taiwan (China)
- Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, 2001 Zonal Avenue, Los Angeles, CA 90033 (United States)
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 {gamma}-H2AX following ionizing irradiation. As a result, the irradiation-induced {gamma}-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.
- OSTI ID:
- 21078010
- Journal Information:
- Virology, Vol. 370, Issue 2; Other Information: DOI: 10.1016/j.virol.2007.08.037; PII: S0042-6822(07)00566-1; Copyright (c) 2007 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0042-6822
- Country of Publication:
- United States
- Language:
- English
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