PARP1-dependent kinetics of recruitment of MRE11 and NBS1 proteins to multiple DNA damage sites

doi:10.1074/jbc.M706734200

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Papers In Press, published online ahead of print November 19, 2007
J. Biol. Chem, 10.1074/jbc.M706734200
Submitted on August 14, 2007
Revised on November 12, 2007
Accepted on November 19, 2007

PARP1-dependent kinetics of recruitment of MRE11 and NBS1 proteins to multiple DNA damage sites

Jean-François Haince, Darin McDonald, Amélie Rodrigue, Ugo Déry, Jean-Yves Masson, Michael J. Hendzel, and Guy G. Poirier

Health and Environment Unit, CHUL Research Center of CHUQ and Laval University, Sainte-Foy, Québec G1V 4G2

Corresponding Author: guy.poirier{at}crchul.ulaval.ca

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 (IR) 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 micro-irradiation in single living cells. We provide direct evidence that PARP1 is able to accumulate at a locally induced DNA double-strand break (DSB). 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 DSB sensors MRE11 and NBS1 in the close vicinity of a DNA lesion. This may explain the sensitivity of cancer cells to PARP inhibitors.

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