The Role of Histone Chaperones in Histone Acetylation and Nucleosome Dynamics

组蛋白伴侣在组蛋白乙酰化和核小体动力学中的作用

• 批准号: 10436253
• 负责人: Andrew Joseph Andrews
• 金额: $ 1.24万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10436253
• 关键词: Acetylation; Acetyltransferase; Affect; Alzheimer' s Disease; Amino Acids; Automobile Driving; Binding; Biochemical; Biological Assay; Bromodomain; Catalytic Domain; Cell Cycle Regulation; Cell Nucleus; Chromatin; Chromatin Modeling; Chromatin Structure; Complex; Computer Models; DNA; DNA Damage; DNA Repair; Data; Decision Making; Disease; EP300 gene; Enzyme Inhibition; Enzymes; Epigenetic Process; Equilibrium; Eukaryotic Cell; Family; Fluorescence; Gene Expression Regulation; Genetic Materials; Genetic Recombination; Genetic Transcription; Genome; Goals; Heart Diseases; Histone Acetylation; Histone H3; Histones; Homologous Gene; Human; Knowledge; Link; Lysine; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Methodological Studies; Modification; Molecular; Molecular Chaperones; Monitor; Mutation; Nucleosomes; Pattern; Positioning Attribute; Post-Translational Protein Processing; Proteins; Regulation; Role; Site; Specificity; System; Testing; Thermodynamics; Work; Yeasts; chromatin modification; drug modification; histone acetyltransferase; histone modification; histone-binding proteins; human disease; in vivo; insight; kinetic model; new therapeutic target; novel; preference; protein complex; recombinational repair; response; success; virtual

PROJECT SUMMARY There is a fundamental paradox within the nucleus of every eukaryotic cell: The genetic material must be organized and compacted yet remain accessible for readout by transcription machinery. Two of the many factors that retain this balance are histones and histone binding proteins. Histones are ultimately responsible for compacting the chromosomal DNA almost 500,000-fold to fit into the nucleus. While genome accessibility is regulated in part by the actions of histone acetyltransferases (KATs), histone chaperones interact directly with histones and can assemble and/or disassemble them on DNA. KATs covalently modify the histones and therefore, have the potential to alter chromatin structure. Exciting new evidence structurally and functionally link KATs and histone chaperones. However, virtually nothing is known about the mechanisms by which these proteins cooperate to manage compaction and genome accessibility. To elucidate these mechanism(s) we are studying the relationships between two families of histone chaperones in yeast and humans, Nap1 and Asf1, and their corresponding KATs, Rtt109 (yeast) and CBP and p300 (human). Rtt109 is the structural homolog of CBP/p300, and both KATs are functionally linked to the Nap1 and Asf1 families of histone chaperones. We have demonstrated the ability of histone chaperones (Asf1), to recognize the acetylation state of histones and work together to modify the specificity of KATs. We are proposing that these chaperones function to maintain the proper acetyl-profiles of chromatin by regulating both which lysines get acetylated and their incorporation in to chromatin. A biochemical and molecular understanding of how specificity and selectivity is achieved is currently a major challenge in the chromatin field. This project will employ and expand on new methodologies for studying complex protein-protein networks needed to regulate chromatin dynamics and post-translational specificity.

项目概要 每个真核细胞的细胞核内都存在一个基本悖论：遗传物质必须是 组织和压缩，但仍然可以通过转录机器读出。众多因​​素中的两个 保持这种平衡的是组蛋白和组蛋白结合蛋白。组蛋白最终负责 将染色体 DNA 压缩近 500,000 倍以适应细胞核。虽然基因组可及性是 组蛋白伴侣部分受组蛋白乙酰转移酶 (KAT) 的作用调节，直接与 组蛋白，并且可以在 DNA 上组装和/或拆卸它们。 KAT 共价修饰组蛋白并 因此，有可能改变染色质结构。令人兴奋的结构和功能联系的新证据 KAT 和组蛋白伴侣。然而，人们对这些现象的机制几乎一无所知。 蛋白质合作管理压缩和基因组可访问性。为了阐明这些机制，我们 研究酵母和人类中两个组蛋白伴侣家族 Nap1 和 Asf1 之间的关系， 及其相应的 KAT、Rtt109（酵母）、CBP 和 p300（人类）。 Rtt109 是结构同系物 CBP/p300 和两种 KAT 在功能上都与组蛋白伴侣的 Nap1 和 Asf1 家族相关。我们有 展示了组蛋白伴侣 (Asf1) 识别组蛋白乙酰化状态并发挥作用的能力 一起修改 KAT 的特异性。我们建议这些伴侣的作用是维持 通过调节赖氨酸的乙酰化及其掺入来调节染色质的适当乙酰基分布 染色质。目前对如何实现特异性和选择性的生化和分子理解 染色质领域的一个重大挑战。该项目将采用并扩展新的研究方法 调节染色质动力学和翻译后特异性所需的复杂蛋白质-蛋白质网络。