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Transcript
Introduction Histone deacetylases(HDACs) modulating chromatin accessibility during transcription, replication, recombination and repair; required for re-establishing chromatin structure on a local basis after transcription of a gene or after the repair of a DNA double-strand break; act during DNA replication when the cellular hitone content is doubled, as these newly synthesized histones are acetylated prior to their deposition onto nascent DNA Hdac3 Class I HDAC associate with the nuclear hormone corepressor SMRT (silencing mediator of retinoid acid and thyroid hormone receptor) and NCOR (nuclear receptor corepressor) Introduction MEFs(murine embryonic fibroblasts) required Hdac3 for cell viability. The observed apoptosis was associated with an impaired S phase progression and DNA double-strand breaks, rather than altered transcriptional programs. The cell function of HDAC3 and its regulatory factors NCOR and SMRT may be the ancestral role and that disruption of these cell cycle funtions may have dramatic consequences for the regulation of chromatin structure and genomic stability. Hdac3 Function Is Required for Efficient DNA Repair In the absence of Hdac3, DNA repair pathways are inefficient The role of Hdac3 in NHEJ and HR DSB repair pathway The role of Hdac3 in NHEJ and HR DSB repair pathway Global changes in histone modifications could contribute to the defects in DNA repair Inactivation of Hdac3 Alters Chromatin Structure and Decreases Global Heterochromatin Inactivation of Hdac3 Alters Chromatin Structure and Decreases Global Heterochromatin Global histone acetylation and methylation marks changes H4K5ac and H4K12ac are commonly associated with histone deposition onto newly synthesized DNA Hdac3 Is Required for Genomic Stability Hdac3 Is Required for Genomic Stability Hdac3-Null Livers Develop Hepatocellular Carcinoma A high mutation rate stimulate the development of HCC Pathway involved in the formation of HCC β-catenin related oncogenic pathway was up-regulated. NCOR1 Is Downregulated in HCC and NCOR and SMRT Regulate Global Histone Acetylation NCOR/SMRT/HDAC3 axis is required for removing histone marks globally and maintaining genomic stability Conclusion • Inactivation of the HDAC3/NCOR/SMRT axis, possibly contibuting to a subset of human cancer by allowing the increase of histone acetylation during the S phase , leading to DNA damage and further accumulation of mutations. • HDIs, when given at too high a dose or for too long, also cause genomic instability in normal cell, leading to therapy-associated secondary cancers. Transient inhibition may be safe.
