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ATM activation by oxidative stress

Zhi Guo1, Sergei Kozlov, Martin F Lavin

  • 1Howard 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.

Science (New York, N.Y.)
|October 23, 2010
PubMed

Insights

Oxidation directly activates the ataxia-telangiectasia mutated (ATM) protein kinase, independent of DNA damage. This discovery reveals ATM as a key sensor of oxidative stress and reactive oxygen species in human cells.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cellular Signaling

Background:

  • The ataxia-telangiectasia mutated (ATM) protein kinase is a key regulator of the DNA damage response, primarily activated by DNA double-strand breaks (DSBs) via the Mre11-Rad50-Nbs1 (MRN) complex.
  • ATM-deficient cells exhibit hypersensitivity to various cellular insults, including oxidative stress, suggesting roles beyond DSB repair.

Purpose of the Study:

  • To investigate the direct activation mechanism of ATM under conditions of oxidative stress.
  • To determine if ATM can be activated independently of DNA double-strand breaks and the MRN complex.

Main Methods:

  • Biochemical assays to detect ATM activation and dimerization.
  • Site-directed mutagenesis of critical cysteine residues in ATM.
  • Cellular assays to assess ATM activation in response to oxidative agents.

Main Results:

  • Oxidation directly induces ATM activation, forming a disulfide-cross-linked dimer, independent of DNA DSBs and the MRN complex.
  • Mutation of a specific cysteine residue abrogated ATM activation via the oxidation pathway.
  • This pathway explains ATM activation observed under oxidative stress conditions.

Conclusions:

  • ATM functions as a direct sensor of reactive oxygen species (ROS).
  • Oxidative modification represents a novel, direct pathway for ATM activation.
  • This finding broadens the understanding of ATM's role in cellular stress response.

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