|Title:||Hepatitis C virus NS3/4A protein interacts with ATM, impairs DNA repair and enhances sensitivity to ionizing radiation||Authors:||Lai C.-K.
|Keywords:||£^-H2AX foci;Ataxia-telangiectasia mutated;DNA repair;Double-strand DNA breaks;Hepatitis C virus;Nonstructural protein NS3/4A;Oncogenesis||Issue Date:||2008||Journal Volume:||370||Journal Issue:||2||Start page/Pages:||295-309||Source:||Virology||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 £^-H2AX following ionizing irradiation. As a result, the irradiation-induced £^-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. ? 2007 Elsevier Inc. All rights reserved.
|Appears in Collections:||植物科學研究所|
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