Understanding the unique properties of the Sin3A histone deacetylase complex in transcription and cell viability

了解 Sin3A 组蛋白脱乙酰酶复合物在转录和细胞活力方面的独特特性

• 批准号: MR/W00190X/1
• 负责人: Shaun Cowley
• 金额: $ 99.78万
• 依托单位: University of Leicester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW00190X%2F1
• 关键词: Understanding; unique; properties; Sin3A; histone

Histone deacetylases (HDACs) are a family of enzymes which help regulate histones, the packaging material for our genetic material, DNA. There are 18 individual HDACs in human cells all with a subtly different functions. Our group studies HDAC1 and HDAC2 (HDAC1/2), two highly related enzymes that are found together as components of large, multi-protein constructs, known as complexes. As part of four distinct complexes, HDAC1/2 helps regulate which of the 20,000 genes in our DNA are switched on, and just as importantly, which ones are switched off. The combination of genes on, and genes off, is what makes each particular cell type unique, and why we don't have teeth in our eyeballs..! Drugs which inhibit HDACs, known as HDAC inhibitors (HDACi) are used to treat epilepsy, depression and leukemia. However, the use of HDACi in patients is associated with debilitating side-effects. Given the positive therapeutic value of HDAC inhibition in numerous diseases, and the detrimental side-effects of our existing drugs, there is a strong imperative to design novel HDACi with improved specificity and alternative modes of action. Our long-term goal is to develop novel inhibitors against each of the four HDAC1/2 complexes using a PROTAC approach, to understand their function in cells and develop novel therapeutics. PROTACs are a new type of drug that both inhibit an enzyme AND cause it to be marked for destruction by the cells internal rubbish disposal system. We have recently published and patented the first PROTACs target against HDAC1/2. To extend this work, we have engineered cells in which a known PROTAC drug is able to target an individual HDAC1/2 complex, known as, Sin3A.Sin3A binds directly to HDAC1 and together they help control the accessibility of DNA, by modifying histones, which helps regulate our genes and maintains DNA integrity. The advantage of our new cells is that we are able to destroy the Sin3A/HDAC1 complex by simply adding a drug to cells. It is degraded in just 2 hours, enabling us to perform experiments that look directly at its role in gene-regulation (switching genes on and off), and in the generation of new DNA strands prior to cell division. In addition, using specific technology known as, mass-spectrometry, we will be able to identify the precise sites of action in histones. By identifying the Sin3A-dependent activity, which genes are affected by its loss, other proteins it interacts with, which sites in histones are modified, we will make significant strides to understanding its role in cells. This information informs the use of HDACi already in use in the clinic, and potentially extends the roles of HDAC1/2 complexes like Sin3A, so that they might be the drug targets of tomorrow.

组蛋白去乙酰化酶（hdac）是一个帮助调节组蛋白的酶家族，组蛋白是我们遗传物质DNA的包装材料。人类细胞中有18个单独的hdac，它们的功能都有细微的不同。我们的研究小组研究了HDAC1和HDAC2 (HDAC1/2)，这两种高度相关的酶是作为大型多蛋白结构（称为复合物）的组成部分一起发现的。作为四种不同复合体的一部分，HDAC1/2有助于调节我们DNA中20,000个基因中的哪些基因被打开，同样重要的是，哪些基因被关闭。基因开启和关闭的结合，使每种特定的细胞类型独一无二，这也是为什么我们的眼球里没有牙齿的原因。抑制HDAC的药物被称为HDAC抑制剂（HDACi），用于治疗癫痫、抑郁症和白血病。然而，在患者中使用HDACi与衰弱的副作用有关。鉴于HDAC抑制在许多疾病中的积极治疗价值，以及我们现有药物的有害副作用，迫切需要设计具有改进特异性和替代作用方式的新型HDAC。我们的长期目标是使用PROTAC方法开发针对四种HDAC1/2复合物的新型抑制剂，以了解它们在细胞中的功能并开发新的治疗方法。PROTACs是一种新型药物，它既能抑制一种酶，又能使其被细胞内部垃圾处理系统标记为要被破坏。我们最近发表了第一个针对hdac /2的PROTACs靶标并申请了专利。为了扩展这项工作，我们设计了一种已知的PROTAC药物能够靶向单个HDAC1/2复合物Sin3A的细胞。Sin3A直接与HDAC1结合，它们一起通过修饰组蛋白来帮助控制DNA的可及性，组蛋白有助于调节我们的基因并维持DNA的完整性。我们的新细胞的优势在于，我们能够通过简单地向细胞中添加药物来破坏Sin3A/HDAC1复合物。它在2小时内降解，使我们能够进行实验，直接观察它在基因调控（开关基因）中的作用，以及在细胞分裂之前产生新的DNA链。此外，使用被称为质谱法的特定技术，我们将能够确定组蛋白中作用的精确位置。通过确定依赖sin3a的活性，哪些基因受到其缺失的影响，与之相互作用的其他蛋白质，组蛋白中的哪些位点被修饰，我们将在理解其在细胞中的作用方面取得重大进展。这一信息为已经在临床上使用的HDACi提供了信息，并有可能扩展HDAC1/2复合物（如Sin3A）的作用，因此它们可能成为未来的药物靶点。

项目成果

Characterization of the HDAC/PI3K inhibitor CUDC-907 as a novel senolytic.

• DOI: 10.18632/aging.204616
• 发表时间: 2023-03-28
• 期刊: AGING-US
• 影响因子: 5.2
• 作者: Al-Mansour, Fares;Alraddadi, Abdullah;He, Buwei;Saleh, Anes;Poblocka, Marta;Alzahrani, Wael;Cowley, Shaun;Macip, Salvador
• 通讯作者: Macip, Salvador

Optimization of Class I Histone Deacetylase PROTACs Reveals that HDAC1/2 Degradation is Critical to Induce Apoptosis and Cell Arrest in Cancer Cells.

• DOI: 10.1021/acs.jmedchem.1c02179
• 发表时间: 2022-04-14
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Smalley JP;Baker IM;Pytel WA;Lin LY;Bowman KJ;Schwabe JWR;Cowley SM;Hodgkinson JT
• 通讯作者: Hodgkinson JT

Comprehensive Transcriptomic Analysis of Novel Class I HDAC Proteolysis Targeting Chimeras (PROTACs).

• DOI: 10.1021/acs.biochem.2c00288
• 发表时间: 2023-02-07
• 期刊: BIOCHEMISTRY
• 影响因子: 2.9
• 作者: Baker, India M.;Smalley, Joshua P.;Sabat, Khadija A.;Hodgkinson, James T.;Cowley, Shaun M.
• 通讯作者: Cowley, Shaun M.

Conflicts with transcription make early replication late.

• DOI: 10.1016/j.molcel.2022.08.026
• 发表时间: 2022-09
• 期刊: Molecular cell
• 影响因子: 16
• 作者: E. Petermann