Human cytomegalovirus inhibits a DNA damage response by mislocalizing checkpoint proteins
Human cytomegalovirus inhibits a DNA damage response by mislocalizing checkpoint proteins
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DOI：
10.1073/pnas.0511148103
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发表时间：
2006-02-21
影响因子：
11.1
通讯作者：
Shenk, T
中科院分区：
文献类型：
--
作者：
Gaspar, M;Shenk, T
DNA损伤检查点途径响应DNA损伤并诱导细胞周期停滞以允许DNA修复的时间。已知几种病毒激活或调节这种细胞反应。在这里，我们表明，共济失调-毛细血管扩张症突变的检查点途径，响应于DNA的双链断裂，被激活，响应于人巨细胞病毒DNA复制。然而，这种激活不会通过该途径传播;它在效应激酶，检查点激酶2（Chk 2）的水平上被阻断。感染后晚期，几种检查点蛋白，包括共济失调-毛细血管扩张突变和Chk 2，被错误定位到细胞质病毒装配区，在那里它们与病毒体结构蛋白共定位。这种共定位通过用识别Chk 2的抗体免疫沉淀病毒体蛋白来证实。病毒复制对电离辐射有抵抗力，电离辐射会导致DNA双链断裂。我们提出，人类CMV DNA复制激活检查点响应DNA双链断裂，和病毒的响应，通过改变本地化的检查点蛋白质的细胞质，从而抑制信号通路。
The DNA damage checkpoint pathway responds to DNA damage and induces a cell cycle arrest to allow time for DNA repair. Several viruses are known to activate or modulate this cellular response. Here we show that the ataxia-telangiectasia mutated checkpoint pathway, which responds to double-strand breaks in DNA, is activated in response to human cytomegalovirus DNA replication. However, this activation does not propagate through the pathway; it is blocked at the level of the effector kinase, checkpoint kinase 2 (Chk2). Late after infection, several checkpoint proteins, including ataxia-telangiectasia mutated and Chk2, are mislocalized to a cytoplasmic virus assembly zone, where they are colocalized with virion structural proteins. This colocalization was confirmed by immunciprecipitation of virion proteins with an antibody that recognizes Chk2. Virus replication was resistant to ionizing radiation, which causes double-strand breaks in DNA. We propose that human CMV DNA replication activates the checkpoint response to DNA double-strand breaks, and the virus responds by altering the localization of checkpoint proteins to the cytoplasm and thereby inhibiting the signaling pathway.