Ataxia telangiectasia mutated (ATM) and ATM and Rad3-related protein exhibit selective target specificities in response to different forms of DNA damage
Ataxia telangiectasia mutated (ATM) and ATM and Rad3-related protein exhibit selective target specificities in response to different forms of DNA damage
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DOI：
10.1074/jbc.m410873200
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发表时间：
2005-01-14
影响因子：
4.8
通讯作者：
O'Reilly, MA
中科院分区：
文献类型：
--
作者：
Helt, CE;Cliby, WA;O'Reilly, MA
共济失调毛细血管扩张突变（ATM）和ATR （ATM和rad3相关）蛋白激酶部分通过磷酸化检查点激酶（Chk） 1、Chk2和p53来延迟细胞周期。已经确定，ATR在紫外线诱导的DNA损伤(如嘧啶二聚体和6-（1,2)-二氢-2-氧-4-嘧啶基-5-甲基-2,4-(1H,3H)-嘧啶二酮）后被激活，而ATM则在双链DNA断裂时被激活。在这里，我们阐明了这些激酶在暴露于IR、UV和高氧（一种导致裂源性DNA损伤的慢性氧化应激条件）的细胞中的激活。在IR氧化损伤后，Chk1（Ser-345）、Chk2（Thr-68）和p53（Ser-15）的磷酸化涉及ATM和ATR。在紫外线辐射诱导的停滞复制分叉中，Chk1和p53的磷酸化需要ATR，而Chk2需要ATM。暴露于高氧的细胞表现出G(1)、S和G(2)的生长延迟，这被wortmannin破坏。与ATM或ATR激活一致，高氧诱导了wortmaninin敏感的Chk1、Chk2和p53磷酸化。通过使用ATM和ATR缺陷细胞，发现Chk1、Chk2和p53的磷酸化依赖于ATM，而ATR也有助于Chk1磷酸化。这些数据显示，激活的ATM和ATR对不同的基因毒性药物表现出选择性底物特异性。
The ataxia telangiectasia mutated (ATM) and ATR (ATM and Rad3-related) protein kinases exert cell cycle delay, in part, by phosphorylating Checkpoint kinase (Chk) 1, Chk2, and p53. It is well established that ATR is activated following UV light-induced DNA damage such as pyrimidine dimers and the 6-(1,2)-dihydro-2-oxo-4-pyrimidinyl-5-methyl-2,4-(1H,3H)-pyrimidinediones, whereas ATM is activated in response to double strand DNA breaks. Here we clarify the activation of these kinases in cells exposed to IR, UV, and hyperoxia, a condition of chronic oxidative stress resulting in clastogenic DNA damage. Phosphorylation on Chk1(Ser-345), Chk2(Thr-68), and p53(Ser-15) following oxidative damage by IR involved both ATM and ATR. In response to ultraviolet radiation-induced stalled replication forks, phosphorylation on Chk1 and p53 required ATR, whereas Chk2 required ATM. Cells exposed to hyperoxia exhibited growth delay in G(1), S, and G(2) that was disrupted by wortmannin. Consistent with ATM or ATR activation, hyperoxia induced wortmannin-sensitive phosphorylation of Chk1, Chk2, and p53. By using ATM- and ATR-defective cells, phosphorylation on Chk1, Chk2, and p53 was found to be ATM-dependent, whereas ATR also contributed to Chk1 phosphorylation. These data reveal activated ATM and ATR exhibit selective substrate specificity in response to different genotoxic agents.