Type B Histone Acetyltransferases and the Assembly of Chromatin Structure

B 型组蛋白乙酰转移酶和染色质结构的组装

• 批准号: 7252463
• 负责人: MARK R PARTHUN
• 金额: $ 29.49万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2010-06-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7252463
• 关键词: Acetylation; Biochemical; Cell Nucleus; Chromatin; Chromatin Modeling; Chromatin Structure; Chromosomes; Class; Complex; DNA; DNA Repair; Defect; Deposition; Development; Disease; Enzymes; Epigenetic Process; Eukaryota; Eukaryotic Cell; Event; Foundations; Genetic; Genetic Recombination; Genetic Transcription; Genomics; Growth and Development function; Histone Acetylation; Histone H3; Histones; In Vitro; Light; Link; Lysine; Malignant Neoplasms; Modification; Molecular; Molecular Chaperones; N-terminal; Nuclear; Numbers; Pathway interactions; Play; Post-Translational Modification Site; Post-Translational Protein Processing; Process; Progress Reports; Proteins; Recruitment Activity; Regulation; Research Personnel; Role; Substrate Specificity; Tail; Transcriptional Regulation; Work; Yeasts; base; cell growth; design; histone acetyltransferase; in vivo; novel; programs; research study

DESCRIPTION (provided by applicant): The assembly of eukaryotic DNA into chromatin structure is essential for the faithful propagation of both the genetic and epigenetic information contained in our chromosomes. In addition, chromatin structure plays an intimate role in the proper progression of key cellular events such as transcription, DNA damage repair and recombination. Bringing together genomic DNA and histone proteins in an orderly manner is a complex process. As defects in chromatin structure are increasingly recognized as a key factor in diseases such as cancer, deciphering the molecular mechanisms at work in the assembly of chromatin is a critical step in developing an understanding of the role chromatin structure plays in the regulation of cell growth and development. One of the earliest events in the chromatin assembly process is the acetylation of lysine residues in the NH2-terminal tail domains of histones H3 and H4 that occurs rapidly following their synthesis. This is a universally conserved aspect of chromatin assembly in eukaryotes. This acetylation is catalyzed by type B histone acetyltransferases (HATs). To date, Hatlp is the only type B HAT that has been identified. We are using this enzyme as a starting point for determining how the acetylation of newly synthesized histones impacts the process of chromatin assembly. A number of recent developments have dramatically altered our picture of type B HATs and are the foundation for the current proposal. Amongst these is the observation that Hat1 p is not exclusively cytoplasmic and can also be found in the nucleus. While in the nucleus, Hatlp is associated with a novel yeast histone chaperone/chromatin assembly factor, Hiflp. In addition, the nuclear Hatlp complex is associated with histone H3 and H4 molecules that contain novel sites of post-translational modification in their globular core domain. We propose to extend these results through the following three specific aims. 1. Investigate the role of the type B histone acetyltransferase Hat1 p in the process of chromatin assembly. 2. Characterize the function of the histone chaperone Hiflp in histone deposition. 3. Characterize core domain modifications on histones H3 and H4 associated with chromatin assembly.

描述（由申请人提供）：真核DNA组装成染色质结构对于我们染色体中所含遗传和表观遗传信息的忠实传播至关重要。此外，染色质结构在关键细胞事件如转录、DNA损伤修复和重组的适当进展中起着密切的作用。将基因组DNA和组蛋白有序地结合在一起是一个复杂的过程。随着染色质结构缺陷越来越被认为是癌症等疾病的关键因素，破译染色质组装中的分子机制是理解染色质结构在细胞生长和发育调控中所起作用的关键步骤。染色质组装过程中最早的事件之一是组蛋白H3和H4的NH 2-末端尾部结构域中的赖氨酸残基的乙酰化，其在合成后迅速发生。这是真核生物中染色质组装的普遍保守的方面。这种乙酰化由B型组蛋白乙酰转移酶（HAT）催化。迄今为止，Hatlp是唯一一种已被鉴定的B型HAT。我们正在使用这种酶作为起点，以确定新合成的组蛋白的乙酰化如何影响染色质组装的过程。最近的一些事态发展极大地改变了我们对B类帽子的看法，是目前提议的基础。其中，观察到Hat 1 p不仅存在于细胞质中，也可以在细胞核中发现。在细胞核中，Hatlp与一种新的酵母组蛋白伴侣/染色质组装因子Hiflp相关。此外，核Hatlp复合物与组蛋白H3和H4分子相关，所述组蛋白H3和H4分子在其球状核心结构域中含有翻译后修饰的新位点。我们建议通过以下三个具体目标来扩展这些结果。1.研究B型组蛋白乙酰转移酶Hat 1 p在染色质组装过程中的作用。2.表征组蛋白伴侣Hiflp在组蛋白沉积中的功能。3.表征与染色质组装相关的组蛋白H3和H4上的核心结构域修饰。