Identification of mammalian Sds3 as an integral component of the Sin3/histone deacetylase corepressor complex
Identification of mammalian Sds3 as an integral component of the Sin3/histone deacetylase corepressor complex
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DOI：
10.1128/mcb.22.8.2743-2750.2002
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发表时间：
2002-04-01
影响因子：
5.3
通讯作者：
DePinho, RA
中科院分区：
文献类型：
--
作者：
Alland, L;David, G;DePinho, RA
基因转录沉默涉及局部染色质修饰，通过局部招募含有组蛋白脱乙酰基酶(HDAC)活性的大分子多蛋白复合体来实现。哺乳动物的辅阻遏子mSin3A和mSin3B通过将HDAC1和2与启动子结合的转录因子捆绑在一起，在这一过程中发挥关键作用。类似的机制似乎也适用于酵母，上位性实验已经确定mSin3和HDAC同源基因(SIN3和RPD3)以及一种新的蛋白质SDS3在相同的阻遏途径中发挥作用。在这里，我们报告了mSin3-HDAC复合体的一个成分的鉴定，它与酵母SDS3同源，在体内与mSin3蛋白物理结合，以一种部分依赖于HDAC活性的方式抑制转录，并在体内启动HDAC1催化活性。酵母SDS3也具有重要的物理和功能特性，这突显了Sin3-HDAC-Sds3复合体在真核细胞生物学中的核心作用，而在哺乳动物细胞中发现mSds3为调节该复合体在人类疾病中的活性提供了一条新的途径。
Silencing of gene transcription involves local chromatin modification achieved through the local recruitment of large multiprotein complexes containing histone deacetylase (HDAC) activity. The mammalian corepressors mSin3A and mSin3B have been shown to play a key role in this process by tethering HDACs 1 and 2 to promoter-bound transcription factors. Similar mechanisms appear to be operative in yeast, in which epistasis experiments have established that the mSin3 and HDAC orthologs (SIN3 and RPD3), along with a novel protein, SDS3, function in the same repressor pathway. Here, we report the identification of a component of the mSin3-HDAC complex that bears homology to yeast SDS3, physically associates with mSin3 proteins in vivo, represses transcription in a manner that is partially dependent on HDAC activity, and enables HDAC1 catalytic activity in vivo. That key physical and functional properties are also shared by yeast SDS3 underscores the central role of the Sin3-HDAC-Sds3 complex in eukaryotic cell biology, and the discovery of mSds3 in mammalian cells provides a new avenue for modulating the activity of this complex in human disease.