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: 10224924
• 负责人: Andrew Joseph Andrews
• 金额: $ 49.86万
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10224924
• 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; Structure; 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.

项目摘要 每个真核细胞的细胞核内都有一个基本的矛盾：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压缩了近50万倍以适应细胞核。虽然基因组可及性是 部分受组蛋白乙酰转移酶（KAT）的作用调节，组蛋白伴侣直接与 组蛋白，并且可以在DNA上组装和/或分解它们。KAT共价修饰组蛋白， 因此，具有改变染色质结构的潜力。令人兴奋的新证据在结构上和功能上 KAT和组蛋白伴侣。然而，几乎没有人知道这些机制， 蛋白质协作以管理压缩和基因组可及性。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Nap 1和Asf 1之间的关系， 以及它们相应的KAT，Rtt 109（酵母）和CBP和p300（人）。Rtt 109是 CBP/p300，这两个KAT功能上与组蛋白伴侣的Nap 1和Asf 1家族相关。我们有 证明了组蛋白伴侣（Asf 1）识别组蛋白乙酰化状态并发挥作用的能力 一起改变KAT的特异性。我们认为这些伴侣的功能是维持 通过调节赖氨酸乙酰化和它们的掺入， 染色质目前，对特异性和选择性如何实现的生物化学和分子理解是 这是染色质领域的一大挑战。该项目将采用和扩展新的研究方法， 复杂的蛋白质-蛋白质网络需要调节染色质动力学和翻译后特异性。