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Molecular and Cellular Biology, April 2005, p. 2770-2784, Vol. 25, No. 7
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.7.2770-2784.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Schizosaccharomyces pombe Swi1, Swi3, and Hsk1 Are Components of a Novel S-Phase Response Pathway to Alkylation Damage{dagger}

Elena Sommariva,1 Till K. Pellny,1 Nilay Karahan,1 Sanjay Kumar,2 Joel A. Huberman,2 and Jacob Z. Dalgaard1*

Marie Curie Research Institute, Oxted, Surrey, United Kingdom,1 Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York2

Received 26 August 2004/ Returned for modification 23 September 2004/ Accepted 20 December 2004

The Swi1 and Swi3 proteins are required for mat1 imprinting and mating-type switching in Schizosaccharomyces pombe, where they mediate a pause of leading-strand replication in response to a lagging-strand signal. In addition, Swi1 has been demonstrated to be involved in the checkpoint response to stalled replication forks, as was described for the Saccharomyces cerevisiae homologue Tof1. This study addresses the roles of Swi1 and Swi3 during a replication process perturbed by the presence of template bases alkylated by methyl methanesulfonate (MMS). Both the swi1 and swi3 mutations have additive effects on MMS sensitivity and on the MMS-induced damage checkpoint response when combined with chk1 and cds1, but they are nonadditive with hsk1. Cells with swi1, swi3, or hsk1 mutations are also defective in slowing progression through S phase in response to MMS damage. Moreover, swi1 and swi3 strains show increased levels of genomic instability even in the absence of exogenously induced DNA damage. Chromosome fragmentation, increased levels of single-stranded DNA, increased recombination, and instability of replication forks stalled in the presence of hydroxyurea are observed, consistent with the possibility that the replication process is affected in these mutants. In conclusion, Swi1, Swi3, and Hsk1 act in a novel S-phase checkpoint pathway that contributes to replication fork maintenance and to survival of alkylation damage.

* Corresponding author. Mailing address: Marie Curie Research Institute, The Chart, Oxted, Surrey RH8 0TL, United Kingdom. Phone: 44 (0) 1883-722-306. Fax: 44 (0) 1883-714-375. E-mail: j.dalgaard{at}mcri.ac.uk.

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

Molecular and Cellular Biology, April 2005, p. 2770-2784, Vol. 25, No. 7
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.7.2770-2784.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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