title: Schizosaccharomyces pombe Swi1, Swi3, and Hsk1 are components of a novel S-phase response pathway to alkylation damage.
abstract: 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.
authors.affiliation: Marie Curie Research Institute, The Chart, Oxted, Surrey RH8 0TL, United Kingdom.
authors.forename: Elena
authors.initials: E
authors.lastname: Sommariva
authors.forename: Till K
authors.initials: TK
authors.lastname: Pellny
authors.forename: Nilay
authors.initials: N
authors.lastname: Karahan
authors.forename: Sanjay
authors.initials: S
authors.lastname: Kumar
authors.forename: Joel A
authors.initials: JA
authors.lastname: Huberman
authors.forename: Jacob Z
authors.initials: JZ
authors.lastname: Dalgaard
mesh_terms: D000478:Alkylation; D018797:Cell Cycle Proteins / Q000378:metabolism*; D004249:DNA Damage; D004271:DNA, Fungal / Q000378:metabolism; D004277:DNA, Single-Stranded / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D016681:Genome, Fungal; D042822:Genomic Instability / Q000235:genetics; D006918:Hydroxyurea / Q000494:pharmacology; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D008938:Mitosis; D009154:Mutation / Q000235:genetics; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016196:S Phase; D012568:Schizosaccharomyces / Q000166:cytology / Q000235:genetics / Q000378:metabolism*; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D004271:DNA, Fungal; D004277:DNA, Single-Stranded; D004268:DNA-Binding Proteins; D029702:Schizosaccharomyces pombe Proteins; C499635:Swi3 protein, S pombe; D014157:Transcription Factors; C513096:swi1 protein, S pombe; D008741:Methyl Methanesulfonate; C094761:HSK1 protein, S pombe; D017346:Protein Serine-Threonine Kinases; D006918:Hydroxyurea