Advanced Computational Modeling of Molecular Machines in Gene Regulation and DNA Repair

基因调控和 DNA 修复中分子机器的高级计算模型

• 批准号: 10576900
• 负责人: Ivaylo Nikolaev Ivanov
• 金额: $ 44.69万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10576900
• 关键词: Aging; Biochemical Pathway; Cancer Etiology; Cells; Cockayne Syndrome; Complex; Computer Models; Coupled; Cryoelectron Microscopy; DNA; DNA Polymerase I; DNA Polymerase II; DNA Polymerase III; DNA Repair; DNA-Directed RNA Polymerase; Data; Defect; Development; Disease; Etiology; Gene Expression; Gene Expression Regulation; Genetic Code; Genetic Diseases; Genetic Transcription; Genomic DNA; Goals; Hereditary Disease; Knowledge; Life; Malignant Neoplasms; Modeling; Molecular; Molecular Machines; Mutation; Nature; Process; Proteins; RNA; Regulation; Regulator Genes; Repair Complex; Science; Structure; Systems Biology; Transcription Factor TFIID; Transcriptional Regulation; Trichothiodystrophy; Work; Xeroderma Pigmentosum; cell growth; cell repository; disease phenotype; effective therapy; environmental change; experimental group; gene function; gene repair; human disease; insight; promoter; response; success; transcription factor TFIIH

PROJECT SUMMARY/ABSTRACT Genomic DNA is the information repository of the cell, encoding the myriad of proteins required to sustain life. To harness this information, cells depend on RNA polymerases - dynamic biomolecular machines that first transcribe the genetic code into RNA. Transcription is a complex and highly regulated process that governs cell growth, differentiation, development and all responses to environmental change. Importantly, the biochemical pathways that orchestrate the expression and repair of genes are intricately intertwined. As a consequence, many human diseases trace their origins to deficiencies in gene regulation or DNA repair. Understanding the molecular-level mechanisms that underlie gene expression and transcription-coupled DNA repair (TCR) is a grand challenge in biomedical science. Progress toward this goal has been hindered by the size, complexity and dynamic nature of the assemblies that accomplish transcription and TCR. In initial studies with our experimental collaborators we combined computational modeling with cryo-electron microscopy data to determine structures of transcription preinitiation complexes (PICs) from all three classes of RNA polymerases (Pol I, Pol II and Pol III). The structures captured the PICs in multiple functional states covering the path from promoter recognition to the formation of a proficient elongation complex. These results offer an unprecedented opportunity for integrative modeling to connect the experimentally observed states, delineate DNA remodeling during the early stages of transcription and uncover the critical mechanisms of transcription regulation. Specifically, we will leverage computational and structural systems biology approaches to 1) determine how the Pol I, II and III transcription machineries recognize and open promoter DNA; 2) examine how the transcription factor TFIID associates with promoter DNA and serves as a platform for assembling the PIC; and 3) uncover the key functions of two recognized TCR master coordinators, transcription factor IIH (TFIIH) and Cockayne Syndrome B protein (CSB). Our work will benefit from synergistic collaborative interactions with world-class experimental groups to inform, validate, and extend our models. Parallel advances in computation and cryo-EM will yield key insights into the structure, dynamics and function of gene regulatory complexes while making direct connection to genetic disease phenotypes. Success of the project will thus have major impacts - both in understanding the etiology of cancers and inherited genetic disorders and in offering a structural framework to devise effective treatments.

项目总结/文摘