Characterizing the Sin3A/HDAC1 complex: an alternative strategy for the precise inhibition of deacetylase activity in cells

组蛋白乙酰化是控制染色质结构和DNA可及性的关键表观遗传机制。乙酰化水平由组蛋白乙酰转移酶（HAT）和组蛋白脱乙酰酶（HDAC）的相反活性控制。细胞中总HDAC活性的大约50%由HDAC 1和HDAC 2（HDAC 1/2）贡献，HDAC 1/2是在四种多蛋白复合物（Sin 3、NuRD、CoREST和MiDAC）之一中发现的高度同源蛋白。掺入这些复合物对HDAC 1/2功能至关重要，因为它们激活酶活性并确定底物特异性。使用敲除和敲低来抑制HDAC 1/2已经表明在细胞周期进程、DNA损伤修复、DNA合成和基因表达调控中起重要作用。HDAC抑制剂在许多疾病状态（癌症、癫痫、神经退行性疾病、HIV感染等）中显示出积极作用。Sin 3含有四个独特的高度保守的PAH结构域，一个四螺旋束，其特异性结合转录因子和染色质相关蛋白。我们假设，通过确定单个PAH结构域在Sin 3A/B复合物活性中的作用，将提供比目前临床上使用的非选择性抑制剂更精确的方式来调节细胞中的HDAC活性。

Histone acetylation is a key epigenetic mechanism controlling chromatin structure and DNA accessibility. The levels of acetylation are controlled by the opposing activities of histone acetyl transferases (HAT) and histone deacetylase (HDAC) enzymes. Approximately 50% of the total HDAC activity in cells is contributed by HDAC1 and HDAC2 (HDAC1/2), highly homologous proteins found in one of four multi-protein complexes (Sin3, NuRD, CoREST and MiDAC). Incorporation into these complexes is crucial for HDAC1/2 function as they activate enzymatic activity and determine substrate specificity. Inhibition of HDAC1/2, using knock-outs and knock-down, has indicated important roles in cell cycle progression, DNA damage repair, DNA synthesis and the regulation of gene expression. HDAC inhibitors have shown positive effects in a number of diseases states (cancer, epilepsy, neurodegenerative disease, HIV infection, etc.). Sin3 contains four unique and highly conserved PAH domains, a four helical bundle, which bind specifically to transcription factors and chromatin associated proteins. We hypothesize, that by establishing a role for individual PAH domains within Sin3A/B complex activities will provide a much more precise way to regulate HDAC activity in cells than the non-selective inhibitors currently used in the clinic.