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Nucleic Acids Research Advance Access originally published online on August 12, 2008
Nucleic Acids Research 2008 36(16):5362-5375; doi:10.1093/nar/gkn503
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Nucleic Acids Research, 2008, Vol. 36, No. 16 5362-5375
© 2008 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.

Genome integrity, repair and replication

Dissecting the role of p53 phosphorylation in homologous recombination provides new clues for gain-of-function mutants

Anja Restle1, Martin Färber1, Cindy Baumann1, Michael Böhringer1, Karl Heinz Scheidtmann2, Carsten Müller-Tidow3 and Lisa Wiesmüller1,2,*

1Department of Obstetrics and Gynecology, University of Ulm, 89075 Ulm, 2Institute for Genetics, University of Bonn, 53113 Bonn and 3Department of Medicine, Hematology/Oncology, University of Münster, 48129 Münster, Germany

*To whom correspondence should be addressed. Tel: +49 731 500 58800; Fax: +49 731 500 58810; Email: lisa.wiesmueller{at}uni-ulm.de

Received June 19, 2008. Revised July 21, 2008. Accepted July 21, 2008.

Regulation of homologous recombination (HR) represents the best-characterized DNA repair function of p53. The role of p53 phosphorylation in DNA repair is largely unknown. Here, we show that wild-type p53 repressed repair of DNA double-strand breaks (DSBs) by HR in a manner partially requiring the ATM/ATR phosphorylation site, serine 15. Cdk-mediated phosphorylation of serine 315 was dispensable for this anti-recombinogenic effect. However, without targeted cleavage of the HR substrate, serine 315 phosphorylation was necessary for the activation of topoisomerase I-dependent HR by p53. Moreover, overexpression of cyclin A1, which mimics the situation in tumors, inappropriately stimulated DSB-induced HR in the presence of oncogenic p53 mutants (not Wtp53). This effect required cyclin A1/cdk-mediated phosphorylation for stable complex formation with topoisomerase I. We conclude that p53 mutants have lost the balance between activation and repression of HR, which results in a net increase of potentially mutagenic DNA rearrangements. Our data provide new insight into the mechanism underlying gain-of-function of mutant p53 in genomic instability.


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[Abstract] [Full Text] [PDF]


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