Activation of Ataxia Telangiectasia-mutated DNA Damage Checkpoint Signal Transduction Elicited by Herpes Simplex Virus Infection*
Activation of Ataxia Telangiectasia-mutated DNA Damage Checkpoint Signal Transduction Elicited by Herpes Simplex Virus Infection*
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DOI：
10.1074/jbc.m500976200
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发表时间：
2005-08
影响因子：
4.8
通讯作者：
Noriko Shirata;A. Kudoh;T. Daikoku;Yasutoshi Tatsumi;M. Fujita;T. Kiyono;Y. Sugaya;Hiroki Isomura;K. Ishizaki;T. Tsurumi
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文献类型：
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作者：
Noriko Shirata;A. Kudoh;T. Daikoku;Yasutoshi Tatsumi;M. Fujita;T. Kiyono;Y. Sugaya;Hiroki Isomura;K. Ishizaki;T. Tsurumi
真核细胞配备有监测和修复受损DNA的机制。单纯疱疹病毒（HSV）DNA复制发生在细胞核的离散位点，即复制区室，病毒复制蛋白聚集并合成大量病毒DNA。在本研究中，发现HSV感染引起细胞DNA损伤反应，激活共济失调-毛细血管扩张突变（ATM）信号转导途径，如ATM的自磷酸化和多个下游靶点（包括Nbs 1，Chk 2和p53）的磷酸化所观察到的，而用UV灭活病毒或复制缺陷型病毒感染则没有。激活的ATM和由Mre 11、Rad 50和Nbs 1组成的DNA损伤传感器MRN复合物被募集并保留在病毒DNA复制的位点，可能将新合成的病毒DNA识别为异常DNA结构。在ATM缺陷细胞中未观察到这些事件，表明ATM依赖性。在Nbs 1缺陷细胞中，HSV感染诱导ATM DNA损伤反应延迟，这表明有效的ATM激活需要功能性MRN复合物。然而，ATM沉默对293 T细胞中的病毒复制没有影响。我们的数据开启了一个有趣的问题，即病毒如何能够完成其复制，尽管宿主细胞激活ATM检查点信号以响应HSV感染。
Eukaryotic cells are equipped with machinery to monitor and repair damaged DNA. Herpes simplex virus (HSV) DNA replication occurs at discrete sites in nuclei, the replication compartment, where viral replication proteins cluster and synthesize a large amount of viral DNA. In the present study, HSV infection was found to elicit a cellular DNA damage response, with activation of the ataxia-telangiectasia-mutated (ATM) signal transduction pathway, as observed by autophosphorylation of ATM and phosphorylation of multiple downstream targets including Nbs1, Chk2, and p53, while infection with a UV-inactivated virus or with a replication-defective virus did not. Activated ATM and the DNA damage sensor MRN complex composed of Mre11, Rad50, and Nbs1 were recruited and retained at sites of viral DNA replication, probably recognizing newly synthesized viral DNAs as abnormal DNA structures. These events were not observed in ATM-deficient cells, indicating ATM dependence. In Nbs1-deficient cells, HSV infection induced an ATM DNA damage response that was delayed, suggesting a functional MRN complex requirement for efficient ATM activation. However, ATM silencing had no effect on viral replication in 293T cells. Our data open up an interesting question of how the virus is able to complete its replication, although host cells activate ATM checkpoint signaling in response to the HSV infection.