Deletion of histone deacetylase 3 reveals critical roles in S phase progression and DNA damage control.
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.
Bhaskara
Srividya
S
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Chyla
Brenda J
BJ
Amann
Joseph M
JM
Knutson
Sarah K
SK
Cortez
David
D
Sun
Zu-Wen
ZW
Hiebert
Scott W
SW
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002110:Caffeine / Q000378:metabolism; D002478:Cells, Cultured; D004249:DNA Damage; D004260:DNA Repair; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis / Q000502:physiology; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000235:genetics / Q000628:therapy; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D010726:Phosphodiesterase Inhibitors / Q000378:metabolism; D011839:Radiation, Ionizing; D016196:S Phase / Q000502:physiology*; D000099186:Histone Deacetylase 3
D002110:Caffeine; D006655:Histone Deacetylases; D010726:Phosphodiesterase Inhibitors; D000099186:Histone Deacetylase 3