ATM-dependent phosphorylation of the checkpoint clamp regulates repair pathways and maintains genomic stability
ATM-dependent phosphorylation of the checkpoint clamp regulates repair pathways and maintains genomic stability
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DOI：
10.4161/cc.20161
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发表时间：
2012-05-01
期刊：
影响因子：
4.3
通讯作者：
Kai, Mihoko
中科院分区：
文献类型：
--
作者：
Shin, Min Hwa;Yuan, Ming;Kai, Mihoko
在遗传毒性应激和正常S期期间，ATM以依赖于Ser272的方式磷酸化检查点钳蛋白Rad9。Ser272是人Rad9中唯一已知的ATM依赖性磷酸化位点。然而，Ser272磷酸化不是DNA损伤后存活或检查点激活所必需的。Ser272的生理功能仍然难以捉摸。在这里，我们表明ATM依赖的Rad9（Ser272）磷酸化需要MRN复合物和控制修复途径。此外，突变细胞积累大量染色体断裂并诱导总染色体重排。我们的研究结果为ATM确立了一个新的和意想不到的作用：它磷酸化检查点钳以控制修复途径，从而在未受干扰的细胞周期和DNA损伤期间保持基因组的完整性。
Upon genotoxic stress and during normal S phase, ATM phosphorylates the checkpoint clamp protein Rad9 in a manner that depends on Ser272. Ser272 is the only known ATM-dependent phosphorylation site in human Rad9. However, Ser272 phosphorylation is not required for survival or checkpoint activation after DNA damage. The physiological function of Ser272 remains elusive. Here, we show that ATM-dependent Rad9(Ser272) phosphorylation requires the MRN complex and controls repair pathways. Furthermore, the mutant cells accumulate large numbers of chromosome breaks and induce gross chromosomal rearrangements. Our findings establish a new and unexpected role for ATM: it phosphorylates the checkpoint clamp in order to control repair pathways, thereby maintaining genomic integrity during unperturbed cell cycle and upon DNA damage.