ATM Activation by Oxidative Stress
ATM Activation by Oxidative Stress
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DOI：
10.1126/science.1192912
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发表时间：
2010-10-22
期刊：
影响因子：
56.9
通讯作者：
Paull, Tanya T.
中科院分区：
文献类型：
--
作者：
Guo, Zhi;Kozlov, Sergei;Paull, Tanya T.
共济失调-毛细血管扩张突变（ATM）蛋白激酶通过Mre 11-Rad 50-Nbs 1（MRN）DNA修复复合物的DNA双链断裂（DSB）激活，并协调启动DNA损伤反应的信号级联。缺乏ATM的细胞也对DSB以外的损伤过敏，特别是氧化应激。我们发现，ATM的氧化直接诱导ATM激活的DNA双链断裂和MRN复合物的情况下。ATM的氧化形式是二硫键交联的二聚体，并且参与二硫键形成的关键半胱氨酸残基的突变特异性地阻断了通过氧化途径的活化。该途径的鉴定解释了在氧化应激条件下ATM活化的观察结果，并表明ATM是人类细胞中活性氧的重要传感器。
The ataxia-telangiectasia mutated (ATM) protein kinase is activated by DNA double-strand breaks (DSBs) through the Mre11-Rad50-Nbs1 (MRN) DNA repair complex and orchestrates signaling cascades that initiate the DNA damage response. Cells lacking ATM are also hypersensitive to insults other than DSBs, particularly oxidative stress. We show that oxidation of ATM directly induces ATM activation in the absence of DNA DSBs and the MRN complex. The oxidized form of ATM is a disulfide-cross-linked dimer, and mutation of a critical cysteine residue involved in disulfide bond formation specifically blocked activation through the oxidation pathway. Identification of this pathway explains observations of ATM activation under conditions of oxidative stress and shows that ATM is an important sensor of reactive oxygen species in human cells.