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Sci. Signal., 5 April 2011
Vol. 4, Issue 167, p. pe18
[DOI: 10.1126/scisignal.2001961]

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All Stressed Out Without ATM Kinase

J. Jefferson P. Perry1,2 and John A. Tainer1,3*

1 Skaggs Institute for Chemical Biology and Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
2 School of Biotechnology, Amrita University, Amritapuri, Clappana P.O, Kollam, Kerala 690525, India.
3 Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.

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.

* Corresponding author. The Scripps Research Institute, La Jolla, CA 92037, USA; fax, (858) 784-2277; e-mail, jat{at}scripps.edu

Citation: J. J. P. Perry, J. A. Tainer, All Stressed Out Without ATM Kinase. Sci. Signal. 4, pe18 (2011).

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THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Signal Transduction by Mitochondrial Oxidants.
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