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.

组蛋白脱乙酰基酶（HDACS）是一个酶家族，有助于调节组蛋白，这是我们遗传材料DNA的包装材料。人类细胞中有18个单独的HDAC，所有HDAC都具有微妙的功能。我们的小组研究HDAC1和HDAC2（HDAC1/2），两种高度相关的酶，它们一起被发现为大型多蛋白构建体的成分，称为复合物。作为四个不同复合物的一部分，HDAC1/2有助于调节我们的DNA中的20,000个基因中的哪些是开启的，并且同样重要的是，哪些基因被关闭。基因上的基因和基因的结合是使每种特定细胞类型都独特的原因，以及为什么我们的眼球没有牙齿。抑制HDAC的药物（称为HDAC抑制剂（HDACI））用于治疗癫痫，抑郁症和白血病。但是，在患者中使用HDACI与衰减的副作用有关。鉴于HDAC抑制在多种疾病中的正治疗值以及现有药物的有害副作用，因此必须强烈设计新颖的HDACI，具有提高的特异性和替代性作用模式。我们的长期目标是使用Protac方法开发针对四个HDAC1/2复合物中每一个的新型抑制剂，以了解它们在细胞中的功能并发展新型治疗剂。 Protac是一种新型药物，既可以抑制酶，又会导致其被细胞内部垃圾处理系统破坏。我们最近发表了针对HDAC1/2的第一个Protac目标。为了扩展这项工作，我们设计了已知的Protac药物能够靶向单个HDAC1/2复合物（称为SIN3A.SIN3A）直接与HDAC1结合的单个HDAC1/2复合物，它们通过修饰组蛋白来帮助控制DNA的可及性，这有助于调节我们的基因和维持DNA的dna完整性。我们新细胞的优点是我们能够通过简单地将药物添加到细胞中来破坏SIN3A/HDAC1复合物。它在短短2个小时内就会降解，使我们能够执行直接研究其在基因调节中的作用（开关和关闭基因）以及细胞分裂之前新的DNA链的作用。此外，使用称为质谱法的特定技术，我们将能够识别组蛋白中的精确作用位点。通过鉴定SIN3A依赖性活性，该活性受其损失影响的基因，与其相互作用的其他蛋白质，其中组蛋白中的位点已修改，我们将迈出显着的步伐，以理解其在细胞中的作用。该信息告知诊所中已经使用的HDACI的使用，并有可能扩展HDAC1/2复合物（如SIN3A）的作用，因此它们可能是明天的药物靶标。

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

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

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.