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Nucleic Acids Research 2006 34(3):1036-1049; doi:10.1093/nar/gkj509
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Published online 9 February 2006

© The Author 2006. Published by Oxford University Press. All rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions{at}oxfordjournals.org

Article

Poly(ADP-RIBOSE) polymerase-1 (Parp-1) antagonizes topoisomerase I-dependent recombination stimulation by P53

Cindy Baumann1, Gisa S. Boehden1,2, Alexander Bürkle3 and Lisa Wiesmüller1,2,*

1Universitätsfrauenklinik, Prittwitzstrasse 43 D-89075 Ulm, Germany 2Heinrich-Pette-Institut für Experimentelle Virologie und Immunologie an der Universität Hamburg Martinistraße 52, D-20251 Hamburg, Germany 3Molecular Toxicology Group, Department of Biology, University of Konstanz D-78457 Konstanz, Germany

*To whom correspondence should be addressed. Tel: +49 731 500 27640; Fax: +49 731 500 26674; Email: lisa.wiesmueller{at}uni-ulm.de

Received December 13, 2005. Revised January 18, 2006. Accepted January 30, 2006.

PARP-1 interacts with and poly(ADP-ribosyl)ates p53 and topoisomerase I, which both participate in DNA recombination. Previously, we showed that PARP-1 downregulates homology-directed double-strand break (DSB) repair. We also discovered that, despite the well-established role of p53 as a global suppressor of error-prone recombination, p53 enhances homologous recombination (HR) at the RAR{alpha} breakpoint cluster region (bcr) comprising topoisomerase I recognition sites. Using an SV40-based assay and isogenic cell lines differing in the p53 and PARP-1 status we demonstrate that PARP-1 counteracts HR enhancement by p53, although DNA replication was largely unaffected. When the same DNA element was integrated in an episomal recombination plasmid, both p53 and PARP-1 exerted anti-recombinogenic rather than stimulatory activities. Strikingly, with DNA substrates integrated into cellular chromosomes, enhancement of HR by p53 and antagonistic PARP-1 action was seen, very similar to the HR of viral minichromosomes. siRNA-mediated knockdown revealed the essential role of topoisomerase I in this regulatory mechanism. However, after I-SceI-meganuclease-mediated cleavage of the chromosomally integrated substrate, no topoisomerase I-dependent effects by p53 and PARP-1 were observed. Our data further indicate that PARP-1, probably through topoisomerase I interactions rather than poly(ADP-ribosyl)ation, prevents p53 from stimulating spontaneous HR on chromosomes via topoisomerase I activity.


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