Mechanisms of ATM Activation

Annu Rev Biochem. 2015;84:711-38. doi: 10.1146/annurev-biochem-060614-034335. Epub 2015 Jan 12.

Abstract

The ataxia-telangiectasia mutated (ATM) protein kinase is a master regulator of the DNA damage response, and it coordinates checkpoint activation, DNA repair, and metabolic changes in eukaryotic cells in response to DNA double-strand breaks and oxidative stress. Loss of ATM activity in humans results in the pleiotropic neurodegeneration disorder ataxia-telangiectasia. ATM exists in an inactive state in resting cells but can be activated by the Mre11-Rad50-Nbs1 (MRN) complex and other factors at sites of DNA breaks. In addition, oxidation of ATM activates the kinase independently of the MRN complex. This review discusses these mechanisms of activation, as well as the posttranslational modifications that affect this process and the cellular factors that affect the efficiency and specificity of ATM activation and substrate phosphorylation. I highlight functional similarities between the activation mechanisms of ATM, phosphatidylinositol 3-kinases (PI3Ks), and the other PI3K-like kinases, as well as recent structural insights into their regulation.

Keywords: ATM; DNA repair; MRN; oxidative stress; signaling.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins / metabolism*
  • DNA-Binding Proteins / metabolism
  • Enzyme Activation
  • Humans
  • Oxidative Stress
  • Phosphatidylinositol 3-Kinase / metabolism
  • Protein Processing, Post-Translational

Substances

  • DNA-Binding Proteins
  • Phosphatidylinositol 3-Kinase
  • Ataxia Telangiectasia Mutated Proteins