title: All stressed out without ATM kinase.
abstract: Ataxia-telangiectasia (A-T) is a rare, neurodegenerative, inherited disease arising from mutations in the kinase A-T mutated (ATM), which promotes cell cycle checkpoints and DNA double-strand break repair. Puzzlingly, these ATM activities fail to fully explain A-T neuropathologies, which instead have links to stress induced by reactive oxygen species (ROS). However, a landmark discovery reveals an unexpected intersection of ROS and kinase signaling: ATM can be directly activated by oxidation to form a disulfide-linked dimer in a mechanism distinct from DNA damage activation. When combined with notable structural-based insights into the ATM homolog DNA-PK (DNA-protein kinase) and mTOR (mammalian target of rapamycin), these results suggest conformation and assembly mechanisms to signal oxidative stress through an ATM nodal point. These findings fundamentally affect our understanding of ROS and ATM signaling and of the A-T phenotype, with implications for altering signaling in cancer cells to increase sensitivities to current therapeutic interventions.
authors.affiliation: Skaggs Institute for Chemical Biology, Department of Molecular Biology, La Jolla, CA 92037, USA.
authors.forename: J Jefferson P
authors.initials: JJ
authors.lastname: Perry
authors.forename: John A
authors.initials: JA
authors.lastname: Tainer
mesh_terms: D001260:Ataxia Telangiectasia / Q000378:metabolism / Q000473:pathology*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000378:metabolism*; D051747:DNA-Activated Protein Kinase / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D019281:Dimerization; D006801:Humans; D008958:Models, Molecular; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000737:chemistry; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D017382:Reactive Oxygen Species; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D051747:DNA-Activated Protein Kinase; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases