ATM Activation by Oxidative Stress

• Published in: Science (American Association for the Advancement of Science) 2010-10, Vol.330 (6003), p.517-521
• Main Authors: Guo, Zhi, Kozlov, Sergei, Lavin, Martin F, Person, Maria D, Paull, Tanya T
• Format: Article
• Language: English
• Subjects: Acid Anhydride Hydrolases; Activation; Animals; Ataxia telangiectasia; Ataxia Telangiectasia - enzymology; Ataxia Telangiectasia - genetics; Ataxia Telangiectasia Mutated Proteins; Automated teller machines; Biological and medical sciences; Cascades; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cellular biology; Cysteine; Cysteine - metabolism; Deoxyribonucleic acid; Dimers; Disulfides; Disulfides - metabolism; DNA; DNA Breaks, Double-Stranded; DNA damage; DNA Repair; DNA Repair Enzymes - genetics; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Enzyme Activation; Fundamental and applied biological sciences. Psychology; Genetic mutation; Humans; Hydrogen Peroxide; Kinases; Lymphocytes; Molecular and cellular biology; MRE11 Homologue Protein; Mutation; Nuclear Proteins - genetics; Oxidation; Oxidative Stress; Pathways; Phosphorylation; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Stresses; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism
• ISSN: 0036-8075; 1095-9203
• 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.