Regulation of non-histone protein functions by histone deacetylases

组蛋白脱乙酰酶（HDAC）是通过催化乙酰基从赖氨酸残基上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，并且在许多涉及染色质的真核生物过程中不可或缺。来自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”脱乙酰酶不仅具有使组蛋白脱乙酰的能力，而且具有使非组蛋白底物脱乙酰的能力。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，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。大约20%的AT患者发展为癌症，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组互补基因（ATDC）最初是基于其补充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。后来的分析显示，ATDC不影响抗辐射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，尽管ATDC基因产物间接地抑制AT细胞的放射敏感性，但ATDC补充AT细胞的机制是不确定的。 AT细胞的放射敏感性以及ATDC的活性和功能是如何调节的是完全未知的。 初步结果表明，ATDC是一个乙酰化的蛋白质，其乙酰化状态是由HDAC9密切控制。为了响应ARRA，这项修订后的提案将测试HDAC9关键参与调节非组蛋白蛋白ATDC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如何调节重要的生物学功能。 通过靶向非组蛋白蛋白的细胞过程。立即重点将放在澄清HDAC9在ATDC蛋白的脱乙酰化，从而影响可能影响AT细胞的放射敏感性的途径的潜在参与。了解ATDC的功能和调节，以及其抑制AT细胞辐射敏感性的机制，将提供重要的见解参与电离辐射的细胞反应的替代途径。此外，异常HDAC与许多人类疾病（如癌症）密切相关。因此，深入了解 HDAC 9在ATDC修饰中的作用不仅将提供对HDAC的新功能和作用机制的深入了解，而且还将提供治疗疾病的潜在诊断和治疗方法。 变更描述： 本订正提案的目标和假设保持不变。因此，修订后的摘要部分的变更极小。

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.