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.

组蛋白脱乙酰酶 (HDAC) 是通过催化去除赖氨酸残基上的乙酰基来调节涉及蛋白质的组蛋白功能的酶，它们在基因转录的调节中发挥着关键作用，并且是许多真核生物过程中不可或缺的染色质结果。研究表明 HDAC 控制细胞周期进程、细胞增殖和分化。值得注意的是，最近的许多研究表明。 “组蛋白”脱乙酰酶不仅能够使组蛋白脱乙酰，还能够使非组蛋白蛋白底物脱乙酰。共济失调性毛细血管扩张症 (AT) 是一种罕见的常染色体隐性遗传性进行性神经退行性儿童疾病，影响大脑和多个其他身体系统。的 AT 患者罹患癌症，最常见的是急性淋巴细胞白血病或淋巴瘤。共济失调性血管扩张 D 组互补基因 (ATDC) 最初是由该基因引起的。后来的分析表明，ATDC 不具有抗辐射性 DNA 合成，并且很可能不会在任何 AT 患者中发生突变。间接抑制 AT 细胞的放射敏感性，这是 ATDC 补充的机制 AT 细胞的放射敏感性以及 ATDC 的活性和功能是如何调节的仍然是完全未知的。初步结果表明 ATDC 是一种乙酰化蛋白，其乙酰化状态受到 HDAC9 的密切控制。此修订提案是为了响应 ARRA，将检验 HDAC9 关键参与调节非组蛋白的活性和功能的总体假设。该项目的长期目标是探索 HDAC9 的新生物学作用，并全面了解 HDAC9 如何调节重要的功能。重点将放在阐明 HDAC9 在 ATDC 蛋白脱乙酰化中的潜在参与，从而影响可能影响 AT 细胞放射敏感性的途径，以及了解 ATDC 的功能和调节。其抑制 AT 细胞放射敏感性的机制将为了解细胞对电离辐射反应的替代途径提供重要见解。此外，异常的 HDAC 与许多人类疾病（例如癌症）密切相关。因此，全面了解 HDAC9 在 ATDC 修饰中的作用不仅将为 HDAC 的新功能和作用机制提供深入的见解，而且还为治疗疾病提供潜在的诊断和治疗方法。变更说明：该修订提案的目标和假设保持不变，因此修订后的摘要部分的变化很小。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The ATDC (TRIM29) protein binds p53 and antagonizes p53-mediated functions.

ATDC (TRIM29) 蛋白结合 p53 并拮抗 p53 介导的功能。

DOI：
发表时间：
2010-06
期刊：
影响因子：
5.3
作者：
Yuan, Zhigang;Villagra, Alejandro;Peng, Lirong;Coppola, Domenico;Glozak, Michele;Sotomayor, Eduardo M;Chen, Jiandong;Lane, William S;Seto, Edward
通讯作者：
Seto, Edward

SIRT1 negatively regulates the activities, functions, and protein levels of hMOF and TIP60.

SIRT1 负向调节 hMOF 和 TIP60 的活性、功能和蛋白质水平。

DOI：
发表时间：
2012-07
期刊：
影响因子：
5.3
作者：
Peng, Lirong;Ling, Hongbo;Yuan, Zhigang;Fang, Bin;Bloom, Gregory;Fukasawa, Kenji;Koomen, John;Chen, Jiandong;Lane, William S;Seto, Edward
通讯作者：
Seto, Edward

Histone deacetylase 9 (HDAC9) regulates the functions of the ATDC (TRIM29) protein.

组蛋白脱乙酰酶 9 (HDAC9) 调节 ATDC (TRIM29) 蛋白的功能。

DOI：
发表时间：
2010-12-10
期刊：
影响因子：
0
作者：
Yuan, Zhigang;Peng, Lirong;Radhakrishnan, Rangasudhagar;Seto, Edward
通讯作者：
Seto, Edward

SIRT1 deacetylates the DNA methyltransferase 1 (DNMT1) protein and alters its activities.

SIRT1 使 DNA 甲基转移酶 1 (DNMT1) 蛋白去乙酰化并改变其活性。

DOI：
发表时间：
2011-12
期刊：
影响因子：
5.3
作者：
Peng, Lirong;Yuan, Zhigang;Ling, Hongbo;Fukasawa, Kenji;Robertson, Keith;Olashaw, Nancy;Koomen, John;Chen, Jiandong;Lane, William S;Seto, Edward
通讯作者：
Seto, Edward

Modulation of histone deacetylase 6 (HDAC6) nuclear import and tubulin deacetylase activity through acetylation.

通过乙酰化调节组蛋白脱乙酰酶 6 (HDAC6) 核输入和微管蛋白脱乙酰酶活性。