The SMRT and N-CoR corepressors are activating cofactors for histone deacetylase 3
The SMRT and N-CoR corepressors are activating cofactors for histone deacetylase 3
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DOI：
10.1128/mcb.21.18.6091-6101.2001
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发表时间：
2001-09-01
影响因子：
5.3
通讯作者：
Lazar, MA
中科院分区：
文献类型：
--
作者：
Guenther, MG;Barak, O;Lazar, MA
基因转录的抑制通过核心组蛋白氨基末端尾部的去乙酰化作用与染色质结构的调控相关联。这一作用由组蛋白去乙酰化酶（HDACs）介导，这些酶在针对受抑制基因启动子的活性多蛋白复合物中发挥作用。在体内，HDAC3与SMRT辅阻遏物形成稳定的复合物。SMRT - HDAC3复合物表现出组蛋白去乙酰化酶活性，而重组HDAC3是一种无活性的酶。在此我们报道SMRT作为HDAC3的激活辅因子发挥作用。相反，SMRT不激活它也与之相互作用的II类HDAC4。HDAC3的激活由一个去乙酰化酶激活结构域（DAD）介导，该结构域包含SMRT中存在的两个SANT基序之一。在相关的辅阻遏物N - CoR中存在一个同源的DAD，它也能激活HDAC3。DAD中的突变若消除与HDAC3的相互作用，也会消除HDAC活性的重建。利用纯化的成分，表明SMRT的DAD对于激活HDAC3是必要且充分的。此外，DAD对于HDAC3发挥酶促功能以及SMRT的主要阻遏功能都是必需的。因此，SMRT和N - CoR不仅仅作为招募HDAC的平台，而且作为细胞中活性HDAC3酶的一个组成部分发挥作用。
Repression of gene transcription is linked to regulation of chromatin structure through deacetylation of core histone amino-terminal tails. This action is mediated by histone deacetylases (HDACs) that function within active multiprotein complexes directed to the promoters of repressed genes. In vivo, HDAC3 forms a stable complex with the SMRT corepressor. The SMRT-HDAC3 complex exhibits histone deacetylase activity, whereas recombinant HDAC3 is an inactive enzyme. Here we report that SMRT functions as an activating cofactor of HDAC3. In contrast, SMRT does not activate the class II HDAC4, with which it also interacts. Activation of HDAC3 is mediated by a deacetylase activating domain (DAD) that includes one of two SANT motifs present in SMRT. A cognate DAD is present in the related corepressor N-CoR, which can also activate HDAC3. Mutations in the DAD that abolish HDAC3 interaction also eliminate reconstitution of HDAC activity. Using purified components, the SMRT DAD is shown to be necessary and sufficient for activation of HDAC3. Moreover, the DAD is required both for HDAC3 to function enzymatically and for the major repression function of SMRT. Thus, SMRT and N-CoR do not serve merely as platforms for HDAC recruitment but function as an integral component of an active cellular HDAC3 enzyme.