HDACs link the DNA damage response, processing of double-strand breaks and autophagy

Nature. 2011 Mar 3;471(7336):74-79. doi: 10.1038/nature09803.

Abstract

Protein acetylation is mediated by histone acetyltransferases (HATs) and deacetylases (HDACs), which influence chromatin dynamics, protein turnover and the DNA damage response. ATM and ATR mediate DNA damage checkpoints by sensing double-strand breaks and single-strand-DNA-RFA nucleofilaments, respectively. However, it is unclear how acetylation modulates the DNA damage response. Here we show that HDAC inhibition/ablation specifically counteracts yeast Mec1 (orthologue of human ATR) activation, double-strand-break processing and single-strand-DNA-RFA nucleofilament formation. Moreover, the recombination protein Sae2 (human CtIP) is acetylated and degraded after HDAC inhibition. Two HDACs, Hda1 and Rpd3, and one HAT, Gcn5, have key roles in these processes. We also find that HDAC inhibition triggers Sae2 degradation by promoting autophagy that affects the DNA damage sensitivity of hda1 and rpd3 mutants. Rapamycin, which stimulates autophagy by inhibiting Tor, also causes Sae2 degradation. We propose that Rpd3, Hda1 and Gcn5 control chromosome stability by coordinating the ATR checkpoint and double-strand-break processing with autophagy.

Publication types

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

MeSH terms

  • Acetylation / drug effects
  • Aminopeptidases / metabolism
  • Autophagy* / drug effects
  • Autophagy-Related Protein 8 Family
  • Autophagy-Related Proteins
  • Chromosomal Instability
  • DNA Breaks, Double-Stranded* / drug effects
  • DNA Repair / drug effects
  • Endodeoxyribonucleases / metabolism
  • Endonucleases / chemistry
  • Endonucleases / metabolism
  • Exodeoxyribonucleases / metabolism
  • Histone Acetyltransferases / metabolism
  • Histone Deacetylase Inhibitors / pharmacology
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism*
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Microtubule-Associated Proteins / metabolism
  • Protein Kinases / genetics
  • Protein Processing, Post-Translational / drug effects
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / metabolism
  • Saccharomyces cerevisiae Proteins / antagonists & inhibitors
  • Saccharomyces cerevisiae Proteins / chemistry
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism
  • Saccharomyces cerevisiae* / cytology
  • Saccharomyces cerevisiae* / enzymology
  • Saccharomyces cerevisiae* / genetics
  • Signal Transduction / drug effects
  • Valproic Acid / pharmacology

Substances

  • ATG8 protein, S cerevisiae
  • Autophagy-Related Protein 8 Family
  • Autophagy-Related Proteins
  • Histone Deacetylase Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • Microtubule-Associated Proteins
  • SAE2 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Valproic Acid
  • GCN5 protein, S cerevisiae
  • Histone Acetyltransferases
  • Protein Kinases
  • ATG1 protein, S cerevisiae
  • MEC1 protein, S cerevisiae
  • Protein-Serine-Threonine Kinases
  • target of rapamycin protein, S cerevisiae
  • Endodeoxyribonucleases
  • Endonucleases
  • Exodeoxyribonucleases
  • MRE11 protein, S cerevisiae
  • exodeoxyribonuclease I
  • Aminopeptidases
  • APE1 protein, S cerevisiae
  • HDA1 protein, S cerevisiae
  • RPD3 protein, S cerevisiae
  • Histone Deacetylases