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Nucleic Acids Research Advance Access published online on September 10, 2009
Nucleic Acids Research, doi:10.1093/nar/gkp748
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© The Author(s) 2009. Published by Oxford University Press.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5/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

Functional significance of the Rad51-Srs2 complex in Rad51 presynaptic filament disruption

Sierra Colavito1, Margaret Macris-Kiss1, Changhyun Seong1, Olive Gleeson2, Eric C. Greene3, Hannah L. Klein2, Lumir Krejci1,4,* and Patrick Sung1,*

1Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520, 2Department of Biochemistry and Kaplan Cancer Center, New York University, School of Medicine, New York, NY 10016, 3Department of Biochemistry and Molecular Biophysics, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA and 4Department of Biology and National Center for Biomolecular Research, Masaryk University, Brno 62500, Czech Republic

*To whom correspondence should be addressed. Tel: +420 549493767; Fax: +420 549492556; Email: lkrejci{at}chemi.muni.czCorrespondence may also be addressed to Patrick Sung. Tel: +1 203 785 4552; Fax: +1 203 785 6404; Email: patrick.sung{at}yale.edu

Received July 20, 2009. Revised August 21, 2009. Accepted August 24, 2009.

The SRS2 (Suppressor of RAD Six screen mutant 2) gene encodes an ATP-dependent DNA helicase that regulates homologous recombination in Saccharomyces cerevisiae. Mutations in SRS2 result in a hyper-recombination phenotype, sensitivity to DNA damaging agents and synthetic lethality with mutations that affect DNA metabolism. Several of these phenotypes can be suppressed by inactivating genes of the RAD52 epistasis group that promote homologous recombination, implicating inappropriate recombination as the underlying cause of the mutant phenotype. Consistent with the genetic data, purified Srs2 strongly inhibits Rad51-mediated recombination reactions by disrupting the Rad51-ssDNA presynaptic filament. Srs2 interacts with Rad51 in the yeast two-hybrid assay and also in vitro. To investigate the functional relevance of the Srs2-Rad51 complex, we have generated srs2 truncation mutants that retain full ATPase and helicase activities, but differ in their ability to interact with Rad51. Importantly, the srs2 mutant proteins attenuated for Rad51 interaction are much less capable of Rad51 presynaptic filament disruption. An internal deletion in Srs2 likewise diminishes Rad51 interaction and anti-recombinase activity. We also present evidence that deleting the Srs2 C-terminus engenders a hyper-recombination phenotype. These results highlight the importance of Rad51 interaction in the anti-recombinase function of Srs2, and provide evidence that this Srs2 function can be uncoupled from its helicase activity.

Present addresses: Margaret Macris-Kiss, Affomix Corporation, 688 East Main St., Branford CT 06405, USA.

Lumir Krejci, Department of Biology and National Center for Biomolecular Research, Masaryk University, Brno 62500, Czech Republic.

Olive Gleeson, Deparment of Biochemistry, National University of Ireland, Galway, Ireland.


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