Deletion of Histone Deacetylase 3 Reveals Critical Roles in S Phase Progression and DNA Damage Control

Mol Cell. 2008 Apr 11;30(1):61-72. doi: 10.1016/j.molcel.2008.02.030.

Abstract

Histone deacetylases (HDACs) are enzymes that modify key residues in histones to regulate chromatin architecture, and they play a vital role in cell survival, cell-cycle progression, and tumorigenesis. To understand the function of Hdac3, a critical component of the N-CoR/SMRT repression complex, a conditional allele of Hdac3 was engineered. Cre-recombinase-mediated inactivation of Hdac3 led to a delay in cell-cycle progression, cell-cycle-dependent DNA damage, and apoptosis in mouse embryonic fibroblasts (MEFs). While no overt defects in mitosis were observed in Hdac3-/- MEFs, including normal H3Ser10 phosphorylation, DNA damage was observed in Hdac3-/- interphase cells, which appears to be associated with defective DNA double-strand break repair. Moreover, we noted that Hdac3-/- MEFs were protected from DNA damage when quiescent, which may provide a mechanistic basis for the action of HDAC inhibitors on cycling tumor cells.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Caffeine / metabolism
  • Cells, Cultured
  • DNA Damage*
  • DNA Repair
  • Fibroblasts / cytology
  • Fibroblasts / physiology
  • Gene Expression Profiling
  • Gene Expression Regulation*
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism*
  • Humans
  • Mice
  • Mice, Knockout
  • Mitosis / physiology
  • NIH 3T3 Cells
  • Neoplasms / genetics
  • Neoplasms / therapy
  • Oligonucleotide Array Sequence Analysis
  • Phenotype
  • Phosphodiesterase Inhibitors / metabolism
  • Radiation, Ionizing
  • S Phase / physiology*

Substances

  • Phosphodiesterase Inhibitors
  • Caffeine
  • Histone Deacetylases
  • histone deacetylase 3