title: Fission yeast Hsk1 (Cdc7) kinase is required after replication initiation for induced mutagenesis and proper response to DNA alkylation damage.
abstract: Genome stability in fission yeast requires the conserved S-phase kinase Hsk1 (Cdc7) and its partner Dfp1 (Dbf4). In addition to their established function in the initiation of DNA replication, we show that these proteins are important in maintaining genome integrity later in S phase and G2. hsk1 cells suffer increased rates of mitotic recombination and require recombination proteins for survival. Both hsk1 and dfp1 mutants are acutely sensitive to alkylation damage yet defective in induced mutagenesis. Hsk1 and Dfp1 are associated with the chromatin even after S phase, and normal response to MMS damage correlates with the maintenance of intact Dfp1 on chromatin. A screen for MMS-sensitive mutants identified a novel truncation allele, rad35 (dfp1-(1-519)), as well as alleles of other damage-associated genes. Although Hsk1-Dfp1 functions with the Swi1-Swi3 fork protection complex, it also acts independently of the FPC to promote DNA repair. We conclude that Hsk1-Dfp1 kinase functions post-initiation to maintain replication fork stability, an activity potentially mediated by the C terminus of Dfp1.
authors.affiliation: Molecular and Computational Biology Program, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: William P
authors.initials: WP
authors.lastname: Dolan
authors.forename: Anh-Huy
authors.initials: AH
authors.lastname: Le
authors.forename: Henning
authors.initials: H
authors.lastname: Schmidt
authors.forename: Ji-Ping
authors.initials: JP
authors.lastname: Yuan
authors.forename: Marc
authors.initials: M
authors.lastname: Green
authors.forename: Susan L
authors.initials: SL
authors.lastname: Forsburg
mesh_terms: D000478:Alkylation / Q000187:drug effects; D000483:Alleles; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D016195:G2 Phase / Q000187:drug effects; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D008954:Models, Biological; D016296:Mutagenesis / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011995:Recombination, Genetic / Q000187:drug effects / Q000235:genetics; D016196:S Phase / Q000187:drug effects; D012568:Schizosaccharomyces / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D002843:Chromatin; D029702:Schizosaccharomyces pombe Proteins; D008741:Methyl Methanesulfonate; D011494:Protein Kinases; C507988:Dfp1 protein, S pombe; C094761:HSK1 protein, S pombe; D017346:Protein Serine-Threonine Kinases