Howard Hughes Medical Institute, Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA.
Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
Sci Signal. 2018 Jan 9;11(512):eaan5598. doi: 10.1126/scisignal.aan5598.
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.
蛋白激酶 ATM 是 DNA 损伤反应的主要调节因子，但也能直接响应氧化应激。ATM 的缺失会导致共济失调毛细血管扩张症，这是一种神经退行性疾病，具有多种症状，包括小脑功能障碍、癌症、糖尿病和早衰。我们使用功能分离突变，将 ATM 通过 DNA 损伤的激活与通过氧化应激的激活进行基因分离。我们发现，Mre11-Rad50-Nbs1 复合物和 DNA 双链断裂导致 ATM 激活不足，会导致细胞活力丧失、检查点激活和 DNA 末端切除，以应对 DNA 损伤。相比之下，氧化激活 ATM 的缺失对与 DNA 损伤相关的结果影响最小，但会阻断 ATM 介导的氧化应激后检查点反应的启动，并导致线粒体功能和自噬缺陷。此外，表达一种不能通过氧化应激激活的 ATM 变体，会导致广泛的蛋白质聚集。这些结果表明，ATM 的激活机制与其对人类细胞代谢和 DNA 损伤反应的影响之间存在直接关系，并暗示 ATM 参与了蛋白质稳态的控制。
