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Molecular and Cellular Biology, July 2005, p. 5738-5751, Vol. 25, No. 13
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.13.5738-5751.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Srs2 and Sgs1 DNA Helicases Associate with Mre11 in Different Subcomplexes following Checkpoint Activation and CDK1-Mediated Srs2 Phosphorylation

Irene Chiolo,¹ Walter Carotenuto,¹ Giulio Maffioletti,^1, John H. J. Petrini,² Marco Foiani,¹ and Giordano Liberi^1*

FIRC Institute of Molecular Oncology Foundation, Via Adamello 16, 20139 Milan, Italy, and Dipartimento di Scienze Biomolecolari e Biotecnologie, Università degli Studi di Milano, Via Celoria 26, 20133 Milan, Italy,¹ Molecular Biology Program, Memorial Sloan Kettering Cancer Center, and Cornell University Graduate School of Medical Sciences, 1275 York Avenue, New York, New York 10021²

Received 25 January 2005/ Returned for modification 24 February 2005/ Accepted 31 March 2005

Mutations in the genes encoding the BLM and WRN RecQ DNA helicases and the MRE11-RAD50-NBS1 complex lead to genome instability and cancer predisposition syndromes. The Saccharomyces cerevisiae Sgs1 RecQ helicase and the Mre11 protein, together with the Srs2 DNA helicase, prevent chromosome rearrangements and are implicated in the DNA damage checkpoint response and in DNA recombination. By searching for Srs2 physical interactors, we have identified Sgs1 and Mre11. We show that Srs2, Sgs1, and Mre11 form a large complex, likely together with yet unidentified proteins. This complex reorganizes into Srs2-Mre11 and Sgs1-Mre11 subcomplexes following DNA damage-induced activation of the Mec1 and Tel1 checkpoint kinases. The defects in subcomplex formation observed in mec1 and tel1 cells can be recapitulated in srs2-7AV mutants that are hypersensitive to intra-S DNA damage and are altered in the DNA damage-induced and Cdk1-dependent phosphorylation of Srs2. Altogether our observations indicate that Mec1- and Tel1-dependent checkpoint pathways modulate the functional interactions between Srs2, Sgs1, and Mre11 and that the Srs2 DNA helicase represents an important target of the Cdk1-mediated cellular response induced by DNA damage.

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

Present address: University of Dundee, Dow Street, Dundee, DD1 5EH, United Kingdom.

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