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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.

http://www.ncbi.nlm.nih.gov/pubmed/17977840

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 RIS Download

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

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Associated grants

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

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