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: 7145376
• 负责人: MARK R PARTHUN
• 金额: $ 30.38万
• 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/7145376
• 关键词: DNA repair; Saccharomyces cerevisiae; acetylation; acyltransferase; chromatin; cytoplasm; enzyme reconstitution; fungal genetics; fungal proteins; gene induction /repression; genetic recombination; genetic regulation; histones; intermolecular interaction; lysine; microarray technology; molecular assembly /self assembly; nucleic acid structure; posttranslational modifications; protein purification; protein structure function; reporter genes; ribosomal DNA; site directed mutagenesis; telomere

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. 1 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 3 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包含的遗传和表观遗传信息的忠实繁殖至关重要。此外，染色质结构在转录、DNA损伤修复和重组等关键细胞事件的正常进行中起着密切的作用。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了解染色质结构在细胞生长和发育中的调节作用的关键一步。染色质组装过程中最早的事件之一是组蛋白H3和H4的nh2末端尾部区域赖氨酸残基的乙酰化，这在它们合成后迅速发生。这是真核生物染色质组装的一个普遍保守的方面。这种乙酰化由B型组蛋白乙酰转移酶（HATs）催化。到目前为止，Hatlp是唯一被确定的B型HAT。我们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过程。最近的一些事态发展极大地改变了我们对B类净化海港计划的看法，它们是目前建议的基础。其中之一是观察到hat1p不仅存在于细胞质中，也可以在细胞核中发现。而在细胞核中，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复合体与组蛋白H3和H4分子相关，组蛋白H3和H4分子在其球状核心区域含有新的翻译后修饰位点。我们建议通过以下3个具体目标来扩展这些成果。1. 探讨B型组蛋白乙酰转移酶hat1p在染色质组装过程中的作用。2. 描述组蛋白伴侣Hiflp在组蛋白沉积中的作用。3. 描述与染色质组装相关的组蛋白H3和H4的核心结构域修饰。