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

基本信息

批准号：
9025255
负责人：
Andrew Joseph Andrews
金额：
$ 10万
依托单位：
RESEARCH INST OF FOX CHASE CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-15 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9025255
关键词：
Acetyl Coenzyme A Acetylation Acetyltransferase Affinity Automobile Driving Binding Biochemical Biochemistry Biological Biological Assay Biological Models Cell Cycle Regulation Cell Nucleus Cells Chromatin Chromatin Modeling Chromatin Structure Complex Coupled DNA DNA Damage DNA Repair Data Dependence Development Disease EP300 gene Enzyme Inhibition Enzymes Epigenetic Process Equilibrium Eukaryotic Cell Figs - dietary Fluorescence Fluorescence Spectrometry Gene Expression Regulation Genetic Materials Genetic Recombination Genetic Transcription Genome Goals Health Histone Acetylation Histone H3 Histone H4 Histones Homologous Gene Human Kinetics Knowledge Link Literature Location Lysine Malignant Neoplasms Mass Spectrum Analysis Measures Methodology Methylation Modeling Modification Molecular Molecular Chaperones Monitor Nucleosomes Positioning Attribute Post-Translational Protein Processing Proteins Reaction Regulation Role Site Specificity Substrate Specificity Tail Techniques Testing Thermodynamics Time Transcriptional Regulation Work Yeasts base dimer drug modification histone acetyltransferase histone modification histone-binding proteins human disease in vitro activity in vivo insight mass spectrometer novel prevent protein complex protein protein interaction quantum response success targeted treatment

项目摘要

DESCRIPTION (provided by applicant): 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 begin to understand this important biological question, this project proposes to study the histone acetyltransferase (KAT) Rtt109 as a model system. Rtt109 employs two structurally unrelated histone chaperones, Vps75 and Asf1. In vivo, Vps75 has been shown to directly interact with Rtt109, but only Asf1 is required for Rtt109 function. Both chaperones activate Rtt109 acetyltransferase activity in vitro, but Rtt109 acetylates histones in multiple locations, and Vps75 and Asf1 appear to alter Rtt109 specificity. 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.

描述（由申请人提供）：每个真核细胞的细胞核内都存在一个基本悖论：遗传物质必须组织和压缩，但仍可通过转录机器读出。保持这种平衡的众多因素中的两个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。虽然基因组可及性部分受组蛋白乙酰转移酶 (KAT) 的作用调节，但组蛋白伴侣直接与组蛋白相互作用，并可以在 DNA 上组装和/或拆卸它们。 KAT 共价修饰组蛋白，因此有可能改变染色质结构。令人兴奋的新证据在结构和功能上将 KAT 和组蛋白伴侣联系起来。然而，实际上我们对这些蛋白质合作管理压缩和基因组可及性的机制一无所知。为了开始了解这一重要的生物学问题，该项目建议研究组蛋白乙酰转移酶 (KAT) Rtt109 作为模型系统。 Rtt109 采用两个结构上不相关的组蛋白伴侣：Vps75 和 Asf1。在体内，Vps75 已被证明可以直接与 Rtt109 相互作用，但 Rtt109 功能仅需要 Asf1。两种伴侣蛋白均在体外激活 Rtt109 乙酰转移酶活性，但 Rtt109 在多个位置乙酰化组蛋白，并且 Vps75 和 Asf1 似乎会改变 Rtt109 特异性。对如何实现特异性和选择性的生化和分子理解是目前染色质领域的主要挑战。该项目将采用并扩展新的方法来研究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。