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Hst3 is regulated by Mec1-dependent proteolysis and controls the S phase checkpoint and sister chromatid cohesion by deacetylating histone H3 at lysine 56.

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.

Pubmed ID: 17977840


  • Thaminy S
  • Newcomb B
  • Kim J
  • Gatbonton T
  • Foss E
  • Simon J
  • Bedalov A


The Journal of biological chemistry

Publication Data

December 28, 2007

Associated Grants

  • Agency: NIDDK NIH HHS, Id: DK56465
  • Agency: NHLBI NIH HHS, Id: HL04211

Mesh Terms

  • Cell Cycle
  • Cell Cycle Proteins
  • Chromatids
  • DNA Damage
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Fungal
  • Histone Deacetylases
  • Histones
  • Intracellular Signaling Peptides and Proteins
  • Lysine
  • Models, Biological
  • Phenotype
  • Phosphorylation
  • Protein-Serine-Threonine Kinases
  • Saccharomyces cerevisiae Proteins
  • Ubiquitin