The sirtuins hst3 and Hst4p preserve genome integrity by controlling histone h3 lysine 56 deacetylation

Curr Biol. 2006 Jul 11;16(13):1280-9. doi: 10.1016/j.cub.2006.06.023.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Amino Acid Sequence
  • Binding Sites
  • Cell Cycle / physiology
  • Cell Cycle Proteins / physiology
  • Chromatin / metabolism
  • DNA Damage
  • DNA Replication
  • Genome, Fungal
  • Genomic Instability
  • Histone Deacetylases / chemistry
  • Histone Deacetylases / genetics
  • Histone Deacetylases / physiology*
  • Histones / metabolism*
  • Lysine / metabolism*
  • Molecular Chaperones
  • Molecular Sequence Data
  • Mutation
  • Niacinamide / metabolism
  • Protein Processing, Post-Translational
  • Saccharomyces cerevisiae / enzymology*
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae Proteins / chemistry
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / physiology*
  • Sequence Alignment
  • Sirtuins / chemistry
  • Sirtuins / genetics
  • Sirtuins / physiology


  • ASF1 protein, S cerevisiae
  • Cell Cycle Proteins
  • Chromatin
  • Histones
  • Molecular Chaperones
  • Saccharomyces cerevisiae Proteins
  • Niacinamide
  • Hst3 protein, S cerevisiae
  • Hst4 protein, S cerevisiae
  • Sirtuins
  • Histone Deacetylases
  • Lysine