Deletion of histone deacetylase 3 reveals critical roles in S phase progression and DNA damage control
Deletion of histone deacetylase 3 reveals critical roles in S phase progression and DNA damage control
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DOI：
10.1016/j.molcel.2008.02.030
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发表时间：
2008-04-11
期刊：
影响因子：
16
通讯作者：
Hiebert, Scott W.
中科院分区：
文献类型：
--
作者：
Bhaskara, Srividya;Chyla, Brenda J.;Hiebert, Scott W.
组蛋白脱乙酰酶(HDAC)是一种修饰组蛋白中关键残基以调节染色质结构的酶，它们在细胞存活、细胞周期进展和肿瘤发生中发挥着至关重要的作用。为了了解N-COR/SMRT阻遏复合体的关键成分HDAC3(-/-)的功能，设计了HDAC3的条件等位基因。重组Cre介导的HDAC3失活导致小鼠胚胎成纤维细胞(MEF)细胞周期进展延迟、细胞周期依赖性DNA损伤和细胞凋亡。虽然在HDAC3(-/-)MEF中没有观察到明显的有丝分裂缺陷，包括正常的H3Ser10磷酸化，但在HDAC3(-/-)间期细胞中观察到了DNA损伤，这似乎与DNA双链断裂修复缺陷有关。此外，我们注意到，HDAC3(-/-)MEF在静止状态下可免受DNA损伤，这可能为HDAC抑制剂对肿瘤细胞周期的作用提供了机制基础。
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-recombinasemediated 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.