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Science 330 (6003): 517-521

Copyright © 2010 by the American Association for the Advancement of Science

ATM Activation by Oxidative Stress

Zhi Guo,1 Sergei Kozlov,2 Martin F. Lavin,2 Maria D. Person,3 Tanya T. Paull1,*

Abstract: The ataxia-telangiectasia mutated (ATM) protein kinase is activated by DNA double-strand breaks (DSBs) through the Mre11-Rad50-Nbs1 (MRN) DNA repair complex and orchestrates signaling cascades that initiate the DNA damage response. Cells lacking ATM are also hypersensitive to insults other than DSBs, particularly oxidative stress. We show that oxidation of ATM directly induces ATM activation in the absence of DNA DSBs and the MRN complex. The oxidized form of ATM is a disulfide–cross-linked dimer, and mutation of a critical cysteine residue involved in disulfide bond formation specifically blocked activation through the oxidation pathway. Identification of this pathway explains observations of ATM activation under conditions of oxidative stress and shows that ATM is an important sensor of reactive oxygen species in human cells.

1 Howard 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.
2 Radiation Biology and Oncology Laboratory, Queensland Institute of Medical Research, and School of Medicine, University of Queensland, Brisbane Q4006, Australia.
3 ICMB Analytical Instrumentation Facility Core, College of Pharmacy, University of Texas at Austin, Austin, TX 78712, USA.

* To whom correspondence should be addressed. E-mail: tpaull{at}mail.utexas.edu


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