title: The sirtuins hst3 and Hst4p preserve genome integrity by controlling histone h3 lysine 56 deacetylation.
abstract: BACKGROUND
  Acetylation of histone H3 lysine 56 (K56Ac) occurs transiently in newly synthesized H3 during passage through S phase and is removed in G2. However, the physiologic roles and effectors of K56Ac turnover are unknown.
  
  
  RESULTS
  The sirtuins Hst3p and, to a lesser extent, Hst4p maintain low levels of K56Ac outside of S phase. In hst3 hst4 mutants, K56 hyperacetylation nears 100%. Residues corresponding to the nicotinamide binding pocket of Sir2p are essential for Hst3p function, and H3 K56 deacetylation is inhibited by nicotinamide in vivo. Rapid inactivation of Hst3/Hst4p prior to S phase elevates K56Ac to 50% in G2, suggesting that K56-acetylated nucleosomes are assembled genome-wide during replication. Inducible expression of Hst3p in G1 or G2 triggers deacetylation of mature chromatin. Cells lacking Hst3/Hst4p exhibit many phenotypes: spontaneous DNA damage, chromosome loss, thermosensitivity, and acute sensitivity to genotoxic agents. These phenotypes are suppressed by mutation of histone H3 K56 into a nonacetylatable residue or by loss of K56Ac in cells lacking the histone chaperone Asf1.
  
  
  CONCLUSIONS
  Our results underscore the critical importance of Hst3/Hst4p in controlling histone H3 K56Ac and thereby maintaining chromosome integrity.
authors.affiliation: High Throughput Biology Center, Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Ivana
authors.initials: I
authors.lastname: Celic
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Masumoto
authors.forename: Wendell P
authors.initials: WP
authors.lastname: Griffith
authors.forename: Pamela
authors.initials: P
authors.lastname: Meluh
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Cotter
authors.forename: Jef D
authors.initials: JD
authors.lastname: Boeke
authors.forename: Alain
authors.initials: A
authors.lastname: Verreault
mesh_terms: D000107:Acetylation; D000595:Amino Acid Sequence; D001665:Binding Sites; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins / Q000502:physiology; D002843:Chromatin / Q000378:metabolism; D004249:DNA Damage; D004261:DNA Replication; D016681:Genome, Fungal; D042822:Genomic Instability; D006655:Histone Deacetylases / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D006657:Histones / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism*; D018832:Molecular Chaperones; D008969:Molecular Sequence Data; D009154:Mutation; D009536:Niacinamide / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D012441:Saccharomyces cerevisiae / Q000201:enzymology* / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D016415:Sequence Alignment; D037761:Sirtuins / Q000737:chemistry / Q000235:genetics / Q000502:physiology
chemical_list: C109731:ASF1 protein, S cerevisiae; D018797:Cell Cycle Proteins; D002843:Chromatin; D006657:Histones; D018832:Molecular Chaperones; D029701:Saccharomyces cerevisiae Proteins; D009536:Niacinamide; C512517:Hst3 protein, S cerevisiae; C512518:Hst4 protein, S cerevisiae; D037761:Sirtuins; D006655:Histone Deacetylases; D008239:Lysine