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Molecular and Cellular Biology, February 2006, p. 976-989, Vol. 26, No. 3
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.3.976-989.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Differential Contributions of Mammalian Rad54 Paralogs to Recombination, DNA Damage Repair, and Meiosis{dagger}

Joanna Wesoly,1 Sheba Agarwal,1 Stefan Sigurdsson,6 Wendy Bussen,6 Stephen Van Komen,6 Jian Qin,7 Harry van Steeg,4 Jan van Benthem,4 Evelyne Wassenaar,2 Willy M. Baarends,2 Mehrnaz Ghazvini,1 Agnieszka A. Tafel,1 Helen Heath,1 Niels Galjart,1 Jeroen Essers,1 J. Anton Grootegoed,2 Norman Arnheim,7 Olga Bezzubova,8 Jean-Marie Buerstedde,8 Patrick Sung,5 and Roland Kanaar1,3*

Department of Cell Biology and Genetics,1 Department of Reproduction and Development,2 Department of Radiation Oncology, Erasmus MC, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands,3 Department of Toxicology, Pathology and Genetics, National Institute of Public Health and The Environment, P.O. Box 1, 3720 BA Bilthoven, The Netherlands,4 Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut 06520,5 Department of Molecular Medicine and Institute of Biotechnology, University of Texas Health Science Center, San Antonio, Texas 78245-3207,6 Molecular and Computational Biology Program, University of Southern California, Los Angeles, California 90089-2910,7 GSF, Institute for Molecular Radiobiology, Neuheberg, Germany8

Received 23 September 2005/ Returned for modification 19 October 2005/ Accepted 1 November 2005

Homologous recombination is a versatile DNA damage repair pathway requiring Rad51 and Rad54. Here we show that a mammalian Rad54 paralog, Rad54B, displays physical and functional interactions with Rad51 and DNA that are similar to those of Rad54. While ablation of Rad54 in mouse embryonic stem (ES) cells leads to a mild reduction in homologous recombination efficiency, the absence of Rad54B has little effect. However, the absence of both Rad54 and Rad54B dramatically reduces homologous recombination efficiency. Furthermore, we show that Rad54B protects ES cells from ionizing radiation and the interstrand DNA cross-linking agent mitomycin C. Interestingly, at the ES cell level the paralogs do not display an additive or synergic interaction with respect to mitomycin C sensitivity, yet animals lacking both Rad54 and Rad54B are dramatically sensitized to mitomycin C compared to either single mutant. This suggests that the paralogs possibly function in a tissue-specific manner. Finally, we show that Rad54, but not Rad54B, is needed for a normal distribution of Rad51 on meiotic chromosomes. Thus, even though the paralogs have similar biochemical properties, genetic analysis in mice uncovered their nonoverlapping roles.

* Corresponding author. Mailing address: Department of Cell Biology and Genetics, Erasmus MC, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands. Phone: 31-10-4087168. Fax: 31-10-4089468. E-mail: r.kanaar{at}erasmusmc.nl.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, February 2006, p. 976-989, Vol. 26, No. 3
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.3.976-989.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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