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All stressed out without ATM kinase

J Jefferson P Perry1, John A Tainer

  • 1Skaggs Institute for Chemical Biology, Department of Molecular Biology, La Jolla, CA 92037, USA.

Science Signaling
|April 7, 2011
PubMed

Insights

Ataxia-telangiectasia (A-T) is linked to reactive oxygen species (ROS) and the ATM kinase. New findings show ATM is activated by oxidation, impacting A-T and cancer therapy.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Genetics

Background:

  • Ataxia-telangiectasia (A-T) is a rare neurodegenerative disease caused by mutations in the ATM kinase.
  • ATM kinase is crucial for cell cycle checkpoints and DNA repair.
  • A-T neuropathology is linked to oxidative stress from reactive oxygen species (ROS), but ATM's role was unclear.

Purpose of the Study:

  • To investigate the intersection of ROS and ATM kinase signaling in A-T.
  • To elucidate the mechanism of ATM activation by oxidative stress.
  • To explore implications for A-T and cancer therapeutics.

Main Methods:

  • Structural insights into ATM homologs (DNA-PK, mTOR).
  • Biochemical assays to detect ATM activation via oxidation.
  • Analysis of ATM dimerization and conformational changes.

Main Results:

  • ATM can be directly activated by oxidation, forming a disulfide-linked dimer.
  • This oxidative activation mechanism is distinct from DNA damage-induced activation.
  • Structural data suggests ATM signaling pathways for oxidative stress.

Conclusions:

  • ATM signaling is directly modulated by oxidative stress through a novel activation mechanism.
  • This discovery reframes understanding of A-T pathogenesis and ATM function.
  • Findings may inform strategies to sensitize cancer cells to therapy.

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