The protein kinase ATM is a master regulator of the DNA damage response but also responds directly to oxidative stress. Loss of ATM causes ataxia telangiectasia, a neurodegenerative disorder with pleiotropic symptoms that include cerebellar dysfunction, cancer, diabetes, and premature aging. We genetically separated the activation of ATM by DNA damage from that by oxidative stress using separation-of-function mutations. We found that deficient activation of ATM by the Mre11-Rad50-Nbs1 complex and DNA double-strand breaks resulted in loss of cell viability, checkpoint activation, and DNA end resection in response to DNA damage. In contrast, loss of oxidative activation of ATM had minimal effects on DNA damage-related outcomes but blocked ATM-mediated initiation of checkpoint responses after oxidative stress and resulted in deficiencies in mitochondrial function and autophagy. In addition, expression of a variant ATM incapable of activation by oxidative stress resulted in widespread protein aggregation. These results indicate a direct relationship between the mechanism of ATM activation and its effects on cellular metabolism and DNA damage responses in human cells and implicate ATM in the control of protein homeostasis.

中文翻译：

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ATM 通过遗传上可分离的途径指导 DNA 损伤反应和蛋白质稳态。


蛋白激酶 ATM 是 DNA 损伤反应的主要调节因子，但也直接对氧化应激做出反应。 ATM 的缺失会导致毛细血管扩张性共济失调，这是一种具有多效性症状的神经退行性疾病，包括小脑功能障碍、癌症、糖尿病和过早衰老。我们利用功能分离突变，从基因上将 DNA 损伤引起的 ATM 激活与氧化应激引起的 ATM 激活分开。我们发现，Mre11-Rad50-Nbs1 复合物对 ATM 的激活不足和 DNA 双链断裂会导致细胞活力丧失、检查点激活和 DNA 损伤引起的 DNA 末端切除。相比之下，ATM 氧化激活的丧失对 DNA 损伤相关结果的影响很小，但会阻止氧化应激后 ATM 介导的检查点反应的启动，并导致线粒体功能和自噬缺陷。此外，不能被氧化应激激活的变异ATM的表达导致了广泛的蛋白质聚集。这些结果表明 ATM 激活机制与其对人体细胞代谢和 DNA 损伤反应的影响之间存在直接关系，并暗示 ATM 参与蛋白质稳态的控制。