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Papers In Press, published online ahead of print March 27, 2004
Molecular Biophysics & Biochemistry, Yale University School of Medicine, New Haven, CT 06520
Corresponding Author: Patrick.Sung{at}yale.edu
Mutants of the Saccharomyces cerevisiae SRS2 gene are hyper-recombinogenic and sensitive to genotoxic agents, and they exhibit synthetic lethality with mutations that compromise DNA repair or other chromosomal processes. In addition, srs2 mutants fail to adapt or recover from DNA damage checkpoint-imposed G2/M arrest. These phenotypic consequences of ablating SRS2 function are effectively overcome by deleting genes of the RAD52 epistasis group that promote homologous recombination, implicating untimely recombination as the underlying cause of the srs2 mutant phenotypes. The SRS2-encoded protein has a ssDNA-dependent ATPase activity, a DNA helicase activity, and an ability to disassemble the Rad51-ssDNA nucleoprotein filament, which is the key catalytic intermediate in Rad51-mediated recombination reactions. To address the role of ATP hydrolysis in Srs2 protein function, we have constructed two mutant variants that are altered in the Walker type A sequence involved in the binding and hydrolysis of ATP. The srs2 K41A and srs2 K41R mutant proteins are both devoid of ATPase and helicase activities and also the ability to displace Rad51 from ssDNA. Accordingly, yeast strains harboring these srs2 mutations are hyper-recombinogenic and sensitive to MMS, and they become inviable upon introducing either the sgs1 or rad54 mutation. These results highlight the importance of the ATP-hydrolysis fueled DNA motor activity in SRS2 functions.
J. Biol. Chem, 10.1074/jbc.M402586200
Submitted on March 8, 2004
Revised on March 27, 2004
Accepted on March 27, 2004
Role of ATP hydrolysis in the anti-recombinase function of Saccharomyces cerevisiae Srs2 protein
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