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J. Biol. Chem., Vol. 280, Issue 2, 1186-1192, January 14, 2005

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Ataxia Telangiectasia Mutated (ATM) and ATM and Rad3-related Protein Exhibit Selective Target Specificities in Response to Different Forms of DNA Damage^*

Christopher E. Helt, William A. Cliby¶, Peter C. Keng||, Robert A. Bambara**, and Michael A. O'Reilly

From the Departments of Environmental Medicine, Pediatrics, ^||Radiation Oncology, and ^**Biochemistry and Biophysics, School of Medicine and Dentistry, the University of Rochester, Rochester, New York 14642 and the ^¶Department of Obstetrics-Gynecology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota 55905

The ataxia telangiectasia mutated (ATM) and ATR (ATM and Rad3-related) protein kinases exert cell cycle delay, in part, by phosphorylating Checkpoint kinase (Chk) 1, Chk2, and p53. It is well established that ATR is activated following UV light-induced DNA damage such as pyrimidine dimers and the 6-(1,2)-dihydro-2-oxo-4-pyrimidinyl-5-methyl-2,4-(1H,3H)-pyrimidinediones, whereas ATM is activated in response to double strand DNA breaks. Here we clarify the activation of these kinases in cells exposed to IR, UV, and hyperoxia, a condition of chronic oxidative stress resulting in clastogenic DNA damage. Phosphorylation on Chk1(Ser-345), Chk2(Thr-68), and p53(Ser-15) following oxidative damage by IR involved both ATM and ATR. In response to ultraviolet radiation-induced stalled replication forks, phosphorylation on Chk1 and p53 required ATR, whereas Chk2 required ATM. Cells exposed to hyperoxia exhibited growth delay in G₁, S, and G₂ that was disrupted by wortmannin. Consistent with ATM or ATR activation, hyperoxia induced wortmannin-sensitive phosphorylation of Chk1, Chk2, and p53. By using ATM- and ATR-defective cells, phosphorylation on Chk1, Chk2, and p53 was found to be ATM-dependent, whereas ATR also contributed to Chk1 phosphorylation. These data reveal activated ATM and ATR exhibit selective substrate specificity in response to different genotoxic agents.

Received for publication, September 21, 2004 , and in revised form, November 5, 2004.

^* This work was supported in part by National Institutes of Health Grants HL-58774 and HL-67392 (to M. A. O'R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by National Institutes of Health Training Grant ES-07026 and HL-66988.

To whom correspondence should be addressed: Dept. of Pediatrics, Box 850, the University of Rochester, 601 Elmwood Ave., Rochester, NY 14642. Tel.: 585-275-5948; Fax: 585-756-7780; E-mail: michael_oreilly{at}urmc.rochester.edu.

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