Article

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

Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Molecular cell (Impact Factor: 14.02). 05/2008; 30(1):61-72. DOI: 10.1016/j.molcel.2008.02.030
Source: PubMed

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.

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Available from: Scott W Hiebert, Jun 15, 2015
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    • "Severely Reduces the Amplitude of Circadian Rhythms To understand the role of Hdac3 in the mammalian circadian clock, we generated a conditional knockout mouse line termed Hdac3 tm1a(EUCOMM)Wtsi (Hdac3 f/f ) using the European Conditional Mouse Mutagenesis Program (EUCOMM) Embryonic Stem Cell Resource (Figure 1A). Because whole-body deletion of Hdac3 results in very early embryonic lethality (Bhaskara et al., 2008), Alb-Cre (Cre recombinase transcription under the control of the Albumin promoter) mice were crossed with Hdac3 f/f mice to generate liver-specific Hdac3 knockout mice (Alb; Hdac3 f/f ) (Knutson et al., 2008). Alb-Cre is expressed in parenchymal liver cells, resulting in roughly 40% recombination hepatocytes at birth and almost complete recombination by 2 weeks after birth (Postic and Magnuson, 2000). "
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    • "The critical importance of corepressor interaction for HDAC3 activity has been recently demonstrated in vivo [172], which shows that mice harboring loss-of-function mutations in the DAD domain of both NCoR and SMRT have essentially no active HDAC3 in all tested tissues, which correlates with globally-increased histone acetylation. These mice, unlike the embryonic lethality of the total HDAC3 knockout mice [173], are vital, suggesting that free HDAC3 is not non-functional. A follow-up study by the Lazar group [174] recently showed that an HDAC3 mutant that is enzymatically inactive "
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    ABSTRACT: Nuclear receptor corepressor (NCoR) and silencing mediator for retinoid and thyroid hormone receptors (SMRT) function as corepressors for diverse transcription factors including nuclear receptors such as estrogen receptors and androgen receptors. Deregulated functions of NCoR and SMRT have been observed in many types of cancers and leukemias. NCoR and SMRT directly bind to transcription factors and nucleate the formation of stable complexes that include histone deacetylase 3, transducin b-like protein 1/TBL1-related protein 1, and G-protein pathway suppressor 2. These NCoR/SMRT-interacting proteins also show deregulated functions in cancers. In this review, we summarize the literature on the mechanism, regulation, and function of the core components of NCoR/SMRT complexes in the context of their involvement in cancers and leukemias. While the current studies support the view that the corepressors are promising targets for cancer treatment, elucidation of the mechanisms of corepressors involved in individual types of cancers is likely required for effective therapy.
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    • "Mechanistically, understanding of how exactly HDAC inhibitors work is not trivial as these inhibitors have global effects on gene expression rather than modulating the expression of a single cancer-relevant gene. In fact, not much is known about functions of HDACs specifically in myeloid development , as global depletion of class I HDAC genes results in early lethality [108] [109] [110], emphasizing their broad functions in the genome. However, at least some specificity can be assumed because conditional knockout studies in mice showed class I HDAC dependency for normal erythroid/megacaryocyte but not for myeloid development [110] [111]. "
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