ATM activation by oxidative stress.
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.
Guo
Zhi
Z
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.
Kozlov
Sergei
S
Lavin
Martin F
MF
Person
Maria D
MD
Paull
Tanya T
TT
D017766:Acid Anhydride Hydrolases; D000818:Animals; D001260:Ataxia Telangiectasia / Q000201:enzymology / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D003545:Cysteine / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004220:Disulfides / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D006861:Hydrogen Peroxide; D000076228:MRE11 Homologue Protein; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D018384:Oxidative Stress; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004220:Disulfides; C121766:MRE11 protein, human; C112156:NBN protein, human; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; D006861:Hydrogen Peroxide; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D000076228:MRE11 Homologue Protein; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D045643:DNA Repair Enzymes; D003545:Cysteine