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Mechanisms of ubiquitin signaling in chromatin-mediated processes

染色质介导过程中泛素信号传导机制

基本信息

批准号：
10582095
负责人：
Cynthia Wolberger
金额：
$ 4.07万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-14 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10582095
关键词：
Acetylation Address Binding Biochemistry Biophysics Cells Chemicals Chromatin Complex Cryoelectron Microscopy DNA DNA Alkylation DNA Repair DNA-Directed RNA Polymerase Defect Deubiquitinating Enzyme Deubiquitination Event Foundations Gene Expression Gene Expression Regulation Genetic Transcription Goals Histone H2B Histone H3 Histones Human Genome Malignant Neoplasms Mediating Methylation Modification Molecular Molecular Chaperones Molecular Machines Monoubiquitination Nucleosomes Pathway interactions Pattern Pharmaceutical Preparations Play Post-Translational Protein Processing Process Proteins Research Role SAGA Signal Transduction Site Ubiquitin Ubiquitination X-Ray Crystallography base chemotherapy design effective therapy genome integrity histone methylation histone modification insight molecular drug target new therapeutic target novel therapeutics programs protein function recruit refractory cancer repair enzyme single molecule tumor

项目摘要

PROJECT SUMMARY Post-translational modifications of the histone proteins that package DNA play a central role in regulating transcription and repair of DNA damage. The goal of this research program is to determine the molecular mechanism by which attachment of the small protein, ubiquitin, to histone proteins functions in concert with modifications including methylation and acetylation to regulate gene expression and maintain genome integrity. Since misregulation of histone ubiquitination and methylation characterizes many cancers, the results of these studies can be used to design new drugs that target the molecular machines involved in these pathways. A major focus of this research program will be on the mechanism by which monoubiquitination of histone H2B triggers a cascade of events needed to activate gene transcription, including methylation of histone H3 and recruitment of histone chaperones that assist RNA polymerase in transcribing DNA through a chromatin template. A combination of x-ray crystallography, cryo-electron microscopy and NMR, single molecule biophysics, solution biochemistry and cell-based approaches will be used to study how coactivator complexes such as SAGA bind their chromatin substrates and combine histone deubiquitination, acetylation and recognition of histone methylation to activate transcription. We will also study the mechanism by which H2B ubiquitination triggers histone methylation and determine the distinct mechanism by which different deubiquitinating enzymes mediate nucleosome dynamics. Another aspect of ubiquitin signaling to be addressed in this program is the mechanism by which ubiquitin chains attached to sites of DNA alkylation damage recruit repair enzymes. The molecular insights that will result from the proposed studies will provide a foundation for developing new chemotherapies that target cancers for which there currently are no effective treatments.

项目总结