Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Cell Cycle. 2012 May 1;11(9):1796-803. doi: 10.4161/cc.20161.
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.
在遗传毒性应激和正常 S 期，ATM 通过依赖 Ser272 的方式磷酸化检查点钳蛋白 Rad9。Ser272 是人类 Rad9 中唯一已知的 ATM 依赖性磷酸化位点。然而，Ser272 磷酸化对于 DNA 损伤后的存活或检查点激活并非必需。Ser272 的生理功能仍然难以捉摸。在这里，我们表明 ATM 依赖性 Rad9(Ser272)磷酸化需要 MRN 复合物并控制修复途径。此外，突变细胞积累大量染色体断裂并诱导染色体结构重排。我们的研究结果确立了 ATM 的一个新的、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 损伤时维持基因组完整性。
