ATM activation in the presence of oxidative stress |
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Authors: | Zhi Guo Rajashree Deshpande Tanya T Paull |
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Institution: | The Howard Hughes Medical Institute; Department of Molecular Genetics and Microbiology; The Institute of Cellular and Molecular Biology; The University of Texas at Austin; Austin, TX USA |
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Abstract: | The Ataxia-Telangiectasia mutated (ATM) kinase is regarded as the major regulator of the cellular response to DNA double strand breaks (DSBs). In response to DSBs, ATM dimers dissociate into active monomers in a process promoted by the Mre11-Rad50-Nbs1 (MRN) complex. ATM can also be activated by oxidative stress directly in the form of exposure to H2O2. The active ATM in this case is a disulfide-crosslinked dimer containing two or more disulfide bonds. Mutation of a critical cysteine residue in the FATC domain involved in disulfide bond formation specifically blocks ATM activation by oxidative stress. Here we show that ATM activation by DSB s is inhibited in the presence of H2O2 because oxidation blocks the ability of MRN to bind to DNA . However, ATM activation via direct oxidation by H2O2 complements the loss of MRN/DSB-dependent activation and contributes significantly to the overall level of ATM activity in the presence of both DSB s and oxidative stress.Key words: ATM, DNA repair, double-strand break, oxidative stress, ROS |
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