Regulation of non-histone protein functions by histone deacetylases

组蛋白脱乙酰酶(HDAC)是一种通过催化赖氨酸残基上乙酰基的去除来调节组蛋白功能的酶。它们在基因转录调控中起着关键作用，在许多涉及染色质的真核生物过程中不可或缺。许多研究结果表明，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”脱乙酰酶不仅能脱乙酰化组蛋白，还能脱乙酰化非组蛋白底物。共济失调毛细血管扩张症(AT)是一种罕见的常染色体隐性、进行性神经退行性儿童疾病，影响大脑和其他多个身体系统。大约20%的AT患者会患上癌症，最常见的是急性淋巴细胞白血病或淋巴瘤。共济失调血管扩张症D组互补(ATDC)基因最初是基于其弥补AT D组成纤维细胞电离辐射敏感性缺陷的能力而被分离出来的。后来的分析显示，ATDC不影响辐射抵抗DNA的合成，并且很可能在任何AT患者中都不会发生突变。因此，虽然ATDC基因产物间接地抑制AT细胞的辐射敏感性，但ATDC补充的机制 AT细胞对辐射的敏感性以及ATDC的活动和功能是如何被调节的完全未知。 初步结果表明，ATDC是一种乙酰化蛋白，其乙酰化状态受HDAC9的密切调控。这项修订后的提案，作为对ARRA的回应，将检验HDAC9关键参与调控非组蛋白ATDC的活动和功能的总体假设。这个项目的长期目标是探索HDAC9的新的生物学作用，并对HDAC9如何调节重要的 以非组蛋白为靶点的细胞过程。目前的重点将放在阐明HDAC9可能参与ATDC蛋白的脱乙酰化，从而影响可能影响AT细胞辐射敏感性的途径。了解ATDC的功能和调控，及其抑制AT细胞辐射敏感性的机制，将为研究参与细胞对电离辐射反应的其他途径提供重要的见解。此外，异常的HDAC与许多人类疾病密切相关，例如癌症。因此，深入了解 HDAC9在ATDC修饰中的作用不仅将为HDACs的新功能和作用机制提供巨大的洞察力，而且将为疾病的治疗提供潜在的诊断和治疗方法。 变更说明： 这项修订提案的目标和假设保持不变。因此，这一修订后的摘要部分只有很小的变化。

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.