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Nucleic Acids Research Advance Access published online on March 21, 2009
Nucleic Acids Research, doi:10.1093/nar/gkp144
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© 2009 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.

Gene Integrity, Repair and Replication

XRCC1 interacts with the p58 subunit of DNA Pol {alpha}-primase and may coordinate DNA repair and replication during S phase

Nicolas Lévy1,2, Maren Oehlmann3, François Delalande4, Heinz Peter Nasheuer3, Alain Van Dorsselaer4, Valérie Schreiber1, Gilbert de Murcia1, Josiane Ménissier-de Murcia1, Domenico Maiorano5,* and Anne Bresson1,*

1FRE 3211, Institut de Recherche de l’École de Biotechnologie de Strasbourg, CNRS/Université de Strasbourg, Ecole Supérieure de Biotechnologie de Strasbourg, Boulevard S. Brant, BP 10413, F-67412, Illkirch Cedex, 2IGBMC, IBGS 1, Rue L. Fries 67404 Illkirch Cedex, France, 3Department of Biochemistry, Cell Cycle Control Laboratory, National University of Ireland, Galway, Ireland, 4Laboratoire de Spectrometrie de Masse Bio-Organique, UMR 7512, CNRS/ULP, ECPM 67087 Strasbourg and 5Surveillance et Stabilité du Génome, UPR 1142, CNRS, Institut de Génétique Humaine, 141, rue de la Cardonille 34396 Cedex 5 Montpellier, France

*To whom correspondence should be addressed. Tel: +33 390 244 700; Fax: +33 390 244 686: Email: anne.bresson{at}esbs.u-strasbg.fr Correspondence may also be addressed to Dr Domenico Maiorano. Tel: +33 499 619 912; Fax: +33 499 619 901; Email: maiorano{at}igh.cnrs.fr

Received January 26, 2009. Revised February 16, 2009. Accepted February 18, 2009.

Repair of single-stranded DNA breaks before DNA replication is critical in maintaining genomic stability; however, how cells deal with these lesions during S phase is not clear. Using combined approaches of proteomics and in vitro and in vivo protein–protein interaction, we identified the p58 subunit of DNA Pol {alpha}-primase as a new binding partner of XRCC1, a key protein of the single strand break repair (SSBR) complex. In vitro experiments reveal that the binding of poly(ADP-ribose) to p58 inhibits primase activity by competition with its DNA binding property. Overexpression of the XRCC1-BRCT1 domain in HeLa cells induces poly(ADP-ribose) synthesis, PARP-1 and XRCC1-BRCT1 poly(ADP-ribosyl)ation and a strong S phase delay in the presence of DNA damage. Addition of recombinant XRCC1-BRCT1 to Xenopus egg extracts slows down DNA synthesis and inhibits the binding of PCNA, but not MCM2 to alkylated chromatin, thus indicating interference with the assembly of functional replication forks. Altogether these results suggest a critical role for XRCC1 in connecting the SSBR machinery with the replication fork to halt DNA synthesis in response to DNA damage.

This article is dedicated to the memory of our colleague Josiane Ménissier-de Murcia who passed away on 15 July 2007.


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