title: DNA replication checkpoint control of Wee1 stability by vertebrate Hsl7.
abstract: G2/M checkpoints prevent mitotic entry upon DNA damage or replication inhibition by targeting the Cdc2 regulators Cdc25 and Wee1. Although Wee1 protein stability is regulated by DNA-responsive checkpoints, the vertebrate pathways controlling Wee1 degradation have not been elucidated. In budding yeast, stability of the Wee1 homologue, Swe1, is controlled by a regulatory module consisting of the proteins Hsl1 and Hsl7 (histone synthetic lethal 1 and 7), which are targeted by the morphogenesis checkpoint to prevent Swe1 degradation when budding is inhibited. We report here the identification of Xenopus Hsl7 as a positive regulator of mitosis that is controlled, instead, by an entirely distinct checkpoint, the DNA replication checkpoint. Although inhibiting Hsl7 delayed mitosis, Hsl7 overexpression overrode the replication checkpoint, accelerating Wee1 destruction. Replication checkpoint activation disrupted Hsl7-Wee1 interactions, but binding was restored by active polo-like kinase. These data establish Hsl7 as a component of the replication checkpoint and reveal that similar cell cycle control modules can be co-opted for use by distinct checkpoints in different organisms.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Yamada
authors.forename: Brad
authors.initials: B
authors.lastname: Duffy
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Perry
authors.forename: Sally
authors.initials: S
authors.lastname: Kornbluth
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D017124:Conserved Sequence / Q000235:genetics; D004261:DNA Replication / Q000235:genetics*; D018076:DNA, Complementary / Q000032:analysis / Q000235:genetics; D005260:Female; D018816:Genes, cdc / Q000502:physiology*; D006801:Humans; D008938:Mitosis / Q000187:drug effects / Q000235:genetics; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D009865:Oocytes; D011494:Protein Kinases / Q000187:drug effects / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D011496:Protein Methyltransferases / Q000235:genetics; D017346:Protein Serine-Threonine Kinases; D011484:Protein-Arginine N-Methyltransferases; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics; D029702:Schizosaccharomyces pombe Proteins; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid; D013045:Species Specificity; D014714:Vertebrates / Q000235:genetics / Q000378:metabolism; D029867:Xenopus Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D014982:Xenopus laevis; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D018076:DNA, Complementary; D009687:Nuclear Proteins; D011494:Protein Kinases; D011496:Protein Methyltransferases; D017346:Protein Serine-Threonine Kinases; D011484:Protein-Arginine N-Methyltransferases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D029701:Saccharomyces cerevisiae Proteins; D029702:Schizosaccharomyces pombe Proteins; D029867:Xenopus Proteins; D000097869:Polo-Like Kinase 1; C400529:PRMT5 protein, human; C495466:Prmt5 protein, Xenopus; C120666:HSL7 protein, S cerevisiae; C099685:SWE1 protein, S cerevisiae; C530005:WEE1 protein, Xenopus; C068689:wee1 protein, S pombe; C499349:WEE1 protein, human