Deletion of histone deacetylase 3 reveals critical roles in S phase progression and DNA damage control.

Bhaskara S, Chyla BJ, Amann JM, Knutson SK, Cortez D, Sun ZW, Hiebert SW
Mol Cell. 2008 30 (1): 61-72

PMID: 18406327 · PMCID: PMC2373760 · DOI:10.1016/j.molcel.2008.02.030

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.

MeSH Terms (21)

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

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