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ATM activation in the presence of oxidative stress

Zhi Guo1, Rajashree Deshpande, Tanya T Paull

  • 1Howard Hughes Medical Institute, University of Texas at Austin, Austin, TX, USA.

Cell Cycle (Georgetown, Tex.)
|December 15, 2010
PubMed

Insights

Oxidative stress inhibits DNA double-strand break (DSB) repair by blocking the MRN complex. However, direct ATM kinase oxidation by H2O2 complements DSB-induced activation, maintaining ATM activity during combined stress.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Biochemistry

Background:

  • The Ataxia-Telangiectasia mutated (ATM) kinase is crucial for DNA double-strand break (DSB) repair.
  • ATM activation typically involves dimer dissociation promoted by the MRN complex upon DSB sensing.
  • Oxidative stress, such as H2O2 exposure, can also activate ATM through disulfide bond formation.

Purpose of the Study:

  • To investigate the interplay between DSB-induced and oxidative stress-induced ATM activation.
  • To elucidate the mechanism by which H2O2 affects MRN complex binding to DNA.
  • To determine the contribution of direct ATM oxidation to overall kinase activity under combined stress conditions.

Main Methods:

  • Investigated ATM activation pathways under varying conditions of DSBs and H2O2 exposure.
  • Utilized molecular assays to assess MRN complex DNA binding.
  • Examined the role of specific cysteine residues in ATM's FATC domain for oxidative activation.

Main Results:

  • H2O2 exposure inhibits MRN complex binding to DNA, thereby impairing DSB-dependent ATM activation.
  • Direct ATM activation via disulfide bond formation by H2O2 can occur independently of MRN.
  • Oxidative ATM activation compensates for impaired DSB-induced activation, ensuring significant kinase activity under combined stress.

Conclusions:

  • ATM activation is complex, involving both DSB-dependent and direct oxidative pathways.
  • Oxidative stress can interfere with DSB repair signaling by disrupting MRN function.
  • Direct ATM oxidation by H2O2 provides a complementary activation mechanism essential for cellular response to combined genotoxic and oxidative insults.

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