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J. Biol. Chem., Vol. 283, Issue 2, 1197-1208, January 11, 2008

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PARP1-dependent Kinetics of Recruitment of MRE11 and NBS1 Proteins to Multiple DNA Damage Sites^*

Jean-François Haince¹, Darin McDonald, Amélie Rodrigue^¶2, Ugo Déry^¶3, Jean-Yves Masson^¶4, Michael J. Hendzel⁵, and Guy G. Poirier⁶

From the Health and Environment Unit, Laval University Hospital Research Center, Centre Hospitalier Universitaire de Québec, Faculty of Medicine, Laval University, Quebec G1V 4G2, Canada, the Department of Oncology, Faculty of Medicine, University of Alberta and Cross Cancer Institute, Alberta T6G 1Z2, Canada and the ^¶Genome Stability Laboratory, Laval University Cancer Research Center, Hôtel-Dieu de Québec, CHUQ, Québec G1R 2J6, Canada

Poly(ADP-ribose) polymerase 1 (PARP1) is a nuclear enzyme that is rapidly activated by DNA strand breaks and signals the presence of DNA lesions by attaching ADP-ribose units to chromatin-associated proteins. The therapeutic applications of PARP inhibitors in potentiating the killing action of ionizing radiation have been well documented and are attracting increasing interest as a cancer treatment. However, the initial kinetics underlying the recognition of multiple DNA lesions by PARP1 and how inhibition of PARP potentiates the activity of DNA-damaging agents are unknown. Here we report the spatiotemporal dynamics of PARP1 recruitment to DNA damage induced by laser microirradiation in single living cells. We provide direct evidence that PARP1 is able to accumulate at a locally induced DNA double strand break. Most importantly, we observed that the rapid accumulation of MRE11 and NBS1 at sites of DNA damage requires PARP1. By determining the kinetics of protein assembly following DNA damage, our study reveals the cooperation between PARP1 and the double strand break sensors MRE11 and NBS1 in the close vicinity of a DNA lesion. This may explain the sensitivity of cancer cells to PARP inhibitors.

Received for publication, August 14, 2007 , and in revised form, November 12, 2007.

^* This work was supported in part 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.

¹ Supported by a scholarship from the CIHR Strategic Training Program grant in genomics, proteomics, and bioinformatics.

² Recipient of a CIHR doctoral scholarship.

³ Recipient of a Fonds de la Recherche en Santé du Québec scholarship.

⁴ A CIHR New Investigator.

⁵ Senior scholar of the Alberta Heritage Foundation for Medical Research.

⁶ Holder of a Canada Research Chair in Proteomics. 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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