Epstein-Barr virus lytic replication elicits ATM checkpoint signal transduction while providing an S-phase-like cellular environment
Epstein-Barr virus lytic replication elicits ATM checkpoint signal transduction while providing an S-phase-like cellular environment
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DOI：
10.1074/jbc.m411405200
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发表时间：
2005-03-04
影响因子：
4.8
通讯作者：
Tsurumi, T
中科院分区：
文献类型：
--
作者：
Kudoh, A;Fujita, M;Tsurumi, T
当暴露于遗传毒性应激时，真核细胞表现出DNA损伤反应，细胞周期进程延迟或停滞，为DNA修复提供时间。EB病毒（EBV）裂解程序的诱导引起细胞DNA损伤反应，激活共济失调毛细血管扩张突变（ATM）信号转导通路。相反，ATM-Rad3相关（ATR）复制检查点途径的激活是最小的。DNA损伤传感器Mre11-Rad50-Nbs1（MRN）复合物和磷酸化ATM被招募并保留在病毒复制区室中，将新合成的病毒DNA识别为异常DNA结构。磷酸化的p53也集中在复制区室中，并与病毒BZLF 1蛋白发生物理相互作用。尽管ATM检查点信号传导被激活，但p53下游信号传导被阻断，S期CDK活性相当高，与裂解性感染的进展相关。因此，尽管宿主细胞响应于裂解病毒DNA合成而激活ATM检查点信号传导，但病毒可以巧妙地逃避这种宿主检查点安全系统，并积极促进有利于病毒裂解复制的S期样环境。
When exposed to genotoxic stress, eukaryotic cells demonstrate a DNA damage response with delay or arrest of cell-cycle progression, providing time for DNA repair. Induction of the Epstein-Barr virus (EBV) lytic program elicited a cellular DNA damage response, with activation of the ataxia telangiectasia-mutated (ATM) signal transduction pathway. Activation of the ATM-Rad3-related (ATR) replication checkpoint pathway, in contrast, was minimal. The DNA damage sensor Mre11-Rad50-Nbs1 (MRN) complex and phosphorylated ATM were recruited and retained in viral replication compartments, recognizing newly synthesized viral DNAs as abnormal DNA structures. Phosphorylated p53 also became concentrated in replication compartments and physically interacted with viral BZLF1 protein. Despite the activation of ATM checkpoint signaling, p53-downstream signaling was blocked, with rather high S-phase CDK activity associated with progression of lytic infection. Therefore, although host cells activate ATM checkpoint signaling with response to the lytic viral DNA synthesis, the virus can skillfully evade this host checkpoint security system and actively promote an S-phase-like environment advantageous for viral lytic replication.