Nucleic Acids Research Advance Access originally published online on November 3, 2007
Nucleic Acids Research 2007 35(22):7665-7675; doi:10.1093/nar/gkm933
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Nucleic Acids Research, 2007, Vol. 35, No. 22 7665-7675
© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Molecular Biology |
Feedback-regulated poly(ADP-ribosyl)ation by PARP-1 is required for rapid response to DNA damage in living cells
1Munich Center for Integrated Protein Science CiPS M, 2Department of Biology, Ludwig Maximilians University Munich, 82152 Planegg-Martinsried, Germany and 3Université Strasbourg 1, Institut Gilbert Laustriat, CNRS - UMR 7175, Département Intégrité du Génome, ESBS, Bld Sébastien Brant, BP 10413, 67412 Illkirch Cedex, France.
*To whom correspondence should be addressed. Tel: +1 49 89 2180 74232; Fax: +1 49 89 2180 74236; Email: h.leonhardt{at}lmu.de, Correspondence may also be addressed to V. Schreiber. Tel: +33 3 90 24 47 04; Fax: +33 3 90 24 46 86; Email: valerie.schreiber{at}esbs.u-strasbg.fr
Received August 8, 2007. Revised October 10, 2007. Accepted October 10, 2007.
Genome integrity is constantly threatened by DNA lesions arising from numerous exogenous and endogenous sources. Survival depends on immediate recognition of these lesions and rapid recruitment of repair factors. Using laser microirradiation and live cell microscopy we found that the DNA-damage dependent poly(ADP-ribose) polymerases (PARP) PARP-1 and PARP-2 are recruited to DNA damage sites, however, with different kinetics and roles. With specific PARP inhibitors and mutations, we could show that the initial recruitment of PARP-1 is mediated by the DNA-binding domain. PARP-1 activation and localized poly(ADP-ribose) synthesis then generates binding sites for a second wave of PARP-1 recruitment and for the rapid accumulation of the loading platform XRCC1 at repair sites. Further PARP-1 poly(ADP-ribosyl)ation eventually initiates the release of PARP-1. We conclude that feedback regulated recruitment of PARP-1 and concomitant local poly(ADP-ribosyl)ation at DNA lesions amplifies a signal for rapid recruitment of repair factors enabling efficient restoration of genome integrity.
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