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. Deletion of histone deacetylase 3 reveals critical roles in S phase progression and DNA damage control. Molecular cell. 2008 Apr 11;30(1). 61-72. PMID: 18406327 [PubMed]. PMCID: PMC2373760. NIHMSID: NIHMS46990.

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.