JBC Transcription and Nuclear Factor Monoclonals

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Originally published In Press as doi:10.1074/jbc.M204409200 on July 31, 2002

J. Biol. Chem., Vol. 277, Issue 41, 38222-38229, October 11, 2002
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ATM Is Activated in Response to N-Methyl-N'-nitro- N-nitrosoguanidine-induced DNA Alkylation*

Aaron W. AdamsonDagger §, Wan-Ju KimDagger , Sanjeev Shangary, R. Baskaran, and Kevin D. BrownDagger ||

From the Dagger  Department of Biochemistry and Molecular Biology and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112 and the  Department of Molecular Genetics and Biochemistry, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15261

p53 plays an important role in response to ionizing radiation by regulating cell cycle progression and triggering apoptosis. These activities are controlled, in part, by the phosphorylation of p53 by the protein kinase ATM. Recent evidence indicates that the monofunctional DNA alkylating agent N-methyl-N'-nitro-N- nitrosoguanidine (MNNG) also triggers up-regulation and phosphorylation of p53; however, the mechanism(s) responsible for this are unknown. We observed that in MNNG-treated normal human fibroblasts, up-regulation and phosphorylation of p53 was sensitive to the ATM kinase inhibitor wortmannin. ATM-deficient fibroblasts exhibited a delay in p53 up-regulation indicating a role for ATM in triggering the MNNG-induced response. Likewise, a mismatch repair (MMR)-deficient colorectal tumor line failed to show rapid up-regulation of p53. However, unlike ATM-deficient cells, these MMR-deficient cells displayed rapid phosphorylation of the p53 residue serine 15 after MNNG. In vitro kinase assays indicate that ATM is rapidly activated in both normal and MMR-deficient cells in response to MNNG. Using a number of morphological and biochemical approaches, we failed to observe MNNG-induced apoptosis in normal human fibroblasts, suggesting that apoptosis-induced DNA strand breaks are not required for the activation of ATM in response to MNNG. Comet assays indicated that strand breaks accumulated, and p53 up-regulation/phosphorylation occurred quite rapidly (within 30 min) after MNNG treatment, suggesting that DNA strand breaks that arise during the repair process activate ATM. These findings indicate that ATM activation is not limited to the ionizing radiation-induced response and potentially plays an important role in response to DNA alkylation.

* This work was supported by Research Project Grant GMC-99198 from the American Cancer Society (to K. D. B.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Supported in part by a predoctoral fellowship from the Stanley S. Scott Cancer Center.

|| To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, LSU Health Sciences Center, 1901 Perdido St., MEB 7101, New Orleans, LA 70112. Tel.: 504-568-2090; Fax: 504-568-3370; E-mail: kbrown1@lsuhsc.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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