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

Sin3A/HDAC1 复合物的表征：精确抑制细胞中脱乙酰酶活性的替代策略

基本信息

批准号：
2098623
负责人：
金额：
--
依托单位：
University of Leicester
依托单位国家：
英国
项目类别：
Studentship
财政年份：
2018
资助国家：
英国
起止时间：
2018 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=studentship-2098623
关键词：
Characterizing Sin3A HDAC1 complex alternative

项目摘要

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.

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)和组蛋白脱乙酰基酶(HDAC)的相反活性控制。细胞中大约50%的HDAC总活性由HDAC1和HDAC2(HDAC1/2)贡献，HDAC1和HDAC2是在四个多蛋白复合体(Sin3，NuRD，Corest和MiDAC)之一中发现的高度同源的蛋白质。掺入这些复合体对HDAC1/2的功能至关重要，因为它们激活了酶活性并决定了底物的特异性。利用基因敲除和敲除抑制HDAC1/2在细胞周期进程、DNA损伤修复、DNA合成和基因表达调控中发挥重要作用。HDAC抑制剂在许多疾病状态(癌症、癫痫、神经退行性疾病、艾滋病毒感染等)中显示出积极的效果。SIN3含有四个独特的高度保守的PAH结构域，一个四螺旋束，与转录因子和染色质相关蛋白特异结合。我们推测，通过在Sin3A/B中建立单个PAH结构域的作用，与目前临床使用的非选择性抑制剂相比，复合活性将提供一种更精确的方式来调节细胞中的HDAC活性。