The sirtuins hst3 and Hst4p preserve genome integrity by controlling histone h3 lysine 56 deacetylation.
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.
Celic
Ivana
I
High Throughput Biology Center, Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Masumoto
Hiroshi
H
Griffith
Wendell P
WP
Meluh
Pamela
P
Cotter
Robert J
RJ
Boeke
Jef D
JD
Verreault
Alain
A
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
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