Howard Hughes Medical Institute, Department of Molecular Genetics and Microbiology, and Institute for Cellular and Molecular Biology (ICMB), University of Texas at Austin, Austin, TX 78712, USA.
Science. 2010 Oct 22;330(6003):517-21. doi: 10.1126/science.1192912.
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.
共济失调毛细血管扩张突变（ATM）蛋白激酶通过 Mre11-Rad50-Nbs1（MRN）DNA 修复复合物被 DNA 双链断裂（DSB）激活，并协调启动 DNA 损伤反应的信号级联反应。缺乏 ATM 的细胞对除 DSB 以外的其他损伤也非常敏感，特别是氧化应激。我们表明，在没有 DNA DSB 和 MRN 复合物的情况下，ATM 的氧化直接诱导 ATM 激活。ATM 的氧化形式是二硫键交联的二聚体，并且涉及二硫键形成的关键半胱氨酸残基的突变特异性地通过氧化途径阻止了激活。该途径的鉴定解释了在氧化应激条件下观察到的 ATM 激活的现象，并表明 ATM 是人类细胞中活性氧的重要传感器。
