Regulation of non-histone protein functions by histone deacetylases

组蛋白脱乙酰酶对非组蛋白功能的调节

基本信息

批准号：
7851182
负责人：
EDWARD SETO
金额：
$ 34.24万
依托单位：
H. LEE MOFFITT CANCER CTR & RES INST
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7851182
关键词：
Acetylation Acute Lymphocytic Leukemia Address Affect Amino Acids Apoptosis Ataxia Telangiectasia Binding Biochemical Biological Biological Process Brain Cell Cycle Progression Cell Nucleus Cell Proliferation Cell Survival Cell physiology Cells Childhood Chromatin Chromatin Modeling Chromosome Segregation Chromosomes Cloning Complement Complement Factor D Complex Coupled Cytoplasm Cytoplasmic Protein DNA DNA biosynthesis Data Deacetylation Defect Diagnostic Disease Enzymes Event Excision Fibroblasts Gene Expression Gene Targeting Genes Genetic Recombination Genetic Transcription Goals HDAC2 gene Hand Histone Acetylation Histone Deacetylase Histone Deacetylation Histones Human Ionizing radiation Laboratories Lymphoma Lysine Malignant Neoplasms Mediating Modification Molecular Mus Mutate Nerve Degeneration Pathway interactions Patients Play Post-Translational Protein Processing Protein Subunits Proteins Radiation Tolerance Regulation Role Site Small Interfering RNA Substrate Specificity TP53 gene Tail Testing Therapeutic Yang abstracting amino group base body system histone deacetylase 3 histone modification insight interest novel prevent protein complex protein function response transcription factor

项目摘要

Histone deacetylases (HDACs) are enzymes that regulate the functions of histone proteins by catalyzing the removal of acetyl groups from lysine residues. They play a pivotal role in the regulation of gene transcription and are indispensable in numerous eukaryotic biological processes involving chromatin. Results from many studies suggest that HDACs control cell cycle progression, cell proliferation, and differentiation. Remarkably, recent studies reveal that many “histone” deacetylases possess the ability to deacetylate not only histones but also non-histone protein substrates. Ataxia telangiectasia (AT) is a rare, autosomal recessive, progressive, neurodegenerative childhood disease that affects the brain and multiple other body systems. About 20% of AT patients develop cancer, most frequently acute lymphocytic leukemia or lymphoma. The ataxiatelangiectasia group D complementing (ATDC) gene was originally isolated on the basis of its ability to complement the ionizing radiation sensitivity defect of AT group D fibroblasts. Later analysis revealed that ATDC does not affect radioresistant DNA synthesis and is most likely not mutated in any AT patients. Therefore, although the ATDC gene product acts indirectly to suppress radiosensitivity in AT cells, the mechanism by which ATDC complements radiosensitivity in AT cells and how ATDC activities and functions are regulated are entirely unknown. Preliminary results indicate that ATDC is an acetylated protein, and its acetylation status is closely controlled by HDAC9. This revised proposal, in response to the ARRA, will test the overall hypothesis that HDAC9 is critically involved in regulating the activities and functions of a non-histone protein, ATDC. The long-term goal of this project is to explore novel biological roles of HDAC9 and to obtain a complete understanding of how HDAC9 regulates important cellular processes by targeting non-histone proteins. Immediate emphasis will be placed on clarifying the potential involvement of HDAC9 in the deacetylation of the ATDC protein that consequently influences a pathway that could affect radiosensitivity in AT cells. Understanding the function and regulation of ATDC, and its mechanism of suppression of radiosensitivity in AT cells, will provide important insights into alternative pathways involved in the cellular response to ionizing radiation. Additionally, abnormal HDACs are strongly correlated with many human maladies, such as cancer. Therefore, a thorough understanding of the role of HDAC9 in the modification of ATDC will provide not only tremendous insight into the novel functions and mechanisms of action of HDACs but also potential diagnostic and therapeutic approaches for the treatment of diseases. Description of changes: The objectives and hypotheses of this revised proposal remain unchanged. As a result, there are minimal changes in this revised abstract section.

组蛋白脱乙酰基酶（HDACS）是通过催化从赖氨酸保留中去除乙酰基基团来调节组蛋白蛋白功能的酶。它们在基因转录的调节中起关键作用，并且在涉及染色质的许多真核生物学过程中是必不可少的。许多研究的结果表明，HDAC控制细胞周期进程，细胞增殖和分化。值得注意的是，最近的研究表明许多 “组蛋白”脱乙酰基酶具有脱乙酰酸的能力，不仅是组蛋白，而且还具有非历史蛋白蛋白底物。催化性毛细血管扩张（AT）是一种罕见的，常染色体隐性的，进行性的，神经退行性的儿童疾病，会影响大脑和多个身体系统。大约20％的患者患癌症，最常见的急性淋巴细胞性白血病或淋巴瘤。原始血管症D组补充（ATDC）基因最初是根据其补充AT D组成纤维细胞的电离辐射敏感性缺陷的能力而分离的。后来的分析表明，ATDC不会影响放射性DNA合成，并且在患者中很可能不会突变。因此，尽管ATDC基因产物间接起作用以抑制细胞中的放射敏感性，但ATDC完成的机制细胞中的放射线敏感性以及如何调节ATDC活性和功能是完全未知的。初步结果表明ATDC是一种乙酰化蛋白，其乙酰化状态由HDAC9密切控制。该修订后的建议是对ARRA的响应，将检验总体假设，即HDAC9关键地参与了调节非内酮蛋白ATDC的活性和功能。该项目的长期目标是探索HDAC9的新生物学作用，并完全了解HDAC9如何调节重要通过靶向非历史蛋白质的细胞过程。立即将重点放在阐明HDAC9在ATDC蛋白上脱乙酰基化中的潜在参与，该蛋白会影响可能影响细胞的放射性敏感性的途径。了解ATDC的功能和调节及其在AT细胞中抑制放射敏性的机理，将为涉及电离辐射的细胞反应涉及的替代途径提供重要的见解。另外，异常HDAC与许多人类疾病（例如癌症）密切相关。因此，对 HDAC9在ATDC修饰中的作用不仅会对HDACS的新功能和作用机理的深刻见解，还提供了用于治疗疾病的潜在诊断和治疗方法。更改的描述：该修订建议的对象和假设保持不变。结果，此修订的摘要部分的变化很小。