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J. Biol. Chem., Vol. 282, Issue 22, 16441-16453, June 1, 2007

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Ataxia Telangiectasia Mutated (ATM) Signaling Network Is Modulated by a Novel Poly(ADP-ribose)-dependent Pathway in the Early Response to DNA-damaging Agents^*

Jean-François Haince¹, Sergei Kozlov, Valina L. Dawson^¶2, Ted M. Dawson^¶23, Michael J. Hendzel^||, Martin F. Lavin, and Guy G. Poirier, Holds a Canada Research Chair in Proteomics⁴

From the Health and Environment Unit, Laval University Hospital Research Center, CHUQ, Faculty of Medicine, Laval University, Quebec, Quebec G1V 4G2, Canada, the Queensland Institute for Medical Research, PO Royal Brisbane Hospital, Brisbane, Queensland 4029, Australia, the ^¶Institute for Cell Engineering and the Departments of Neurology and Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, and the ^||Department of Oncology, Faculty of Medicine, University of Alberta and Cross Cancer Institute, Edmonton, Alberta T6G 1Z2, Canada

Poly(ADP-ribosyl)ation is a post-translational modification that is instantly stimulated by DNA strand breaks creating a unique signal for the modulation of protein functions in DNA repair and cell cycle checkpoint pathways. Here we report that lack of poly(ADP-ribose) synthesis leads to a compromised response to DNA damage. Deficiency in poly(ADP-ribosyl)ation metabolism induces profound cellular sensitivity to DNA-damaging agents, particularly in cells deficient for the protein kinase ataxia telangiectasia mutated (ATM). At the biochemical level, we examined the significance of poly(ADP-ribose) synthesis on the regulation of early DNA damage-induced signaling cascade initiated by ATM. Using potent PARP inhibitors and PARP-1 knock-out cells, we demonstrate a functional interplay between ATM and poly(ADP-ribose) that is important for the phosphorylation of p53, SMC1, and H2AX. For the first time, we demonstrate a functional and physical interaction between the major DSB signaling kinase, ATM and poly(ADP-ribosyl)ation by PARP-1, a key enzyme of chromatin remodeling. This study suggests that poly(ADP-ribose) might serve as a DNA damage sensory molecule that is critical for early DNA damage signaling.

Received for publication, August 31, 2006 , and in revised form, April 10, 2007.

^* This work was supported by the Canadian Institutes of Health Research (CIHR). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ Supported by a scholarship from the CIHR Strategic Training Program Grant in Genomics, Proteomics, and Bioinformatics.

² Supported by NINDS, National Institutes of Health Grant NS39148.

³ The Leonard and Madlyn Abramson Professor in Neurodegenerative Diseases.

⁴ To whom correspondence should be addressed: CHUL Rm. RC-9700, 2705, Laurier Blvd., Quebec, Quebec G1V 4G2, Canada. Tel.: 418-654-2267; Fax: 418-654-2159; E-mail: guy.poirier{at}crchul.ulaval.ca.

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