title: Hst3 is regulated by Mec1-dependent proteolysis and controls the S phase checkpoint and sister chromatid cohesion by deacetylating histone H3 at lysine 56.
abstract: The SIR2 homologues HST3 and HST4 have been implicated in maintenance of genome integrity in the yeast Saccharomyces cerevisiae. We find that Hst3 has NAD-dependent histone deacetylase activity in vitro and that it functions during S phase to deacetylate the core domain of histone H3 at lysine 56 (H3K56). In response to genotoxic stress, Hst3 undergoes rapid Mec1-dependent phosphorylation and is targeted for ubiquitin-mediated proteolysis, thus providing a mechanism for the previously observed checkpoint-dependent accumulation of Ac-H3K56 at sites of DNA damage. Loss of Hst3-mediated regulation of H3K56 acetylation results in a defect in the S phase DNA damage checkpoint. The pathway that regulates H3K56 acetylation acts in parallel with the Rad9 pathway to transmit a DNA damage signal from Mec1 to Rad53. We also observe that loss of Hst3 function impairs sister chromatid cohesion (SCC). Both S phase checkpoint and SCC defects are phenocopied by H3K56 point mutants. Our findings demonstrate that Hst3-regulated H3K56 acetylation safeguards genome stability by controlling the S phase DNA damage response and promoting SCC.
authors.affiliation: Clinical Research Division and Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Safia
authors.initials: S
authors.lastname: Thaminy
authors.forename: Benjamin
authors.initials: B
authors.lastname: Newcomb
authors.forename: Jessica
authors.initials: J
authors.lastname: Kim
authors.forename: Tonibelle
authors.initials: T
authors.lastname: Gatbonton
authors.forename: Eric
authors.initials: E
authors.lastname: Foss
authors.forename: Julian
authors.initials: J
authors.lastname: Simon
authors.forename: Antonio
authors.initials: A
authors.lastname: Bedalov
mesh_terms: D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism; D002842:Chromatids / Q000235:genetics*; D004249:DNA Damage; D015971:Gene Expression Regulation, Enzymologic; D015966:Gene Expression Regulation, Fungal; D006655:Histone Deacetylases / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D006657:Histones / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D008239:Lysine / Q000737:chemistry*; D008954:Models, Biological; D010641:Phenotype; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D029701:Saccharomyces cerevisiae Proteins / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D029701:Saccharomyces cerevisiae Proteins; D025801:Ubiquitin; C069930:rad9 protein; C088937:MEC1 protein, S cerevisiae; D017346:Protein Serine-Threonine Kinases; C512517:Hst3 protein, S cerevisiae; D006655:Histone Deacetylases; D008239:Lysine