Hepatitis C virus NS3/4A protein interacts with ATM, impairs DNA repair and enhances sensitivity to ionizing radiation
Hepatitis C virus NS3/4A protein interacts with ATM, impairs DNA repair and enhances sensitivity to ionizing radiation
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DOI：
10.1016/j.virol.2007.08.037
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发表时间：
2008-01-20
期刊：
影响因子：
3.7
通讯作者：
Lai, Michael M. C.
中科院分区：
文献类型：
--
作者：
Lai, Chao-Kuen;Jeng, King-Song;Lai, Michael M. C.
丙型肝炎病毒(HCV)感染常与肝细胞癌和非霍奇金B细胞淋巴瘤的发生有关。丙型肝炎病毒非结构蛋白3(NS3)具有丝氨酸蛋白酶、核苷三磷酸酶和解旋酶活性，而NS4A是NS3丝氨酸蛋白酶的辅因子。在这里，我们展示了丙型肝炎病毒NS3/4A与ATM(共济失调-毛细血管扩张突变)的相互作用，ATM是细胞对辐射反应所必需的细胞蛋白。NS3/4A的表达导致电离辐射后内源或外源ATM的胞浆移位，以及磷酸化ATM和γ-H_2AX的延迟去磷酸化。结果，在表达NS3/4A的细胞中，辐射诱导的伽马-H_2AX焦点持续时间更长。此外，在单细胞电泳法中，这些细胞的彗星尾距增加，表明双链DNA断裂增加。携带丙型肝炎病毒复制子的细胞也显示出ATM的细胞质定位，并增加了对辐射的敏感性。这些结果表明，NS3/4A通过与ATM相互作用降低了DNA修复的效率，使细胞对DNA损伤更加敏感。这种作用可能与丙型肝炎病毒的致癌作用有关。(C)2007 Elsevier Inc.保留所有权利。
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. (c) 2007 Elsevier Inc. All rights reserved.