组蛋白伴侣在组蛋白乙酰化和核小体动力学中的作用-猫眼课题宝

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：

10641905

负责人：

Andrew Joseph Andrews

金额：

$39.73万

依托单位：

UNIVERSITY OF NORTH CAROLINA WILMINGTON

依托单位国家：

美国

项目类别：

财政年份：

2014

资助国家：

美国

项目状态：

未结题

起止时间：

2014-09-15 至 2025-06-30

来源：

https://reporter.nih.gov/project-details/10641905

关键词：

Acetylation Acetyltransferase Affect Alzheimer&apos s Disease Amino Acids Automobile Driving Binding Biochemical Biological Assay Bromodomain Catalytic Domain Cell Cycle Regulation Cell Nucleus Chromatin Chromatin Assembly and Disassembly 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 improved in vivo insight kinetic model new therapeutic target novel preference programs protein complex recombinational repair response success virtual

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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.

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