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Structural and Biochemical Analyses of Type II DNA Topoisomerases

II 型 DNA 拓扑异构酶的结构和生化分析

基本信息

批准号：
10112833
负责人：
JAMES M BERGER
金额：
$ 45.47万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-05-01 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10112833
关键词：
3-Dimensional ATP phosphohydrolase Address Adopted Anti-Bacterial Agents Antineoplastic Agents Architecture Area Binding Biochemical Biochemistry Biological Biology Catalytic Domain Cell Survival Cell physiology Cells Chemicals Chromosome Structures Chromosomes Clinical Color Communicable Diseases Complex DNA DNA Damage DNA topoisomerase II alpha Data Development Disease Drug Targeting Electron Microscopy Elements Enzymes Etiology Eukaryotic Cell Event Funding Gene Expression Genes Genetic Genetic Transcription Goals Health Homologous Gene Housekeeping Human Hybrids Image Knowledge Label Lead Left Ligand Binding Link Malignant Neoplasms Mass Spectrum Analysis Meiosis Meiotic Recombination Methodology Modeling Molecular Machines Mutation Outcome Pathway interactions Physiological Positioning Attribute Process Production Proteins Regulation Reporting Reproduction Research Route SPO11 gene Shapes Site Structure Superhelical DNA System Testing Therapeutic Intervention Topoisomerase Topoisomerase II Topoisomerase Inhibitors Transcriptional Activation Variant Work Yeasts base cancer cell dimer enzyme activity field study genetic information genome integrity in vivo inhibitor/antagonist insight molecular dynamics mutant paralogous gene programs promoter recombinase response scaffold

项目摘要

ABSTRACT The appropriate control of DNA topology has a major impact on the stability and flow of genetic information. The present application focuses on type II topoisomerases, molecular machines that modulate DNA supercoiling and remove chromosome entanglements by catalyzing the ATP-dependent transport of one DNA duplex through another. Type II topoisomerases are critical for maintaining gene expression, chromosome superstructure, and genome integrity; they also serve as frontline drug targets for treating infectious disease and cancer. During the prior project period, we gained several new insights into the mechanism, regulation, and DNA damage propensity of type II topoisomerases. These efforts open up three new research opportunities centered on complementary but non-interdependent aspects of type II topoisomerase action that will advance both fundamental biological knowledge and therapeutic intervention. Aim 1 seeks to explain the long-unresolved question of how type II topoisomerases link ATP-dependent allosteric responses to the selective engagement and release of multiple DNA segments, and to illuminate how a system responsible for initiating meiotic recombination co-opted and modified a topoisomerase scaffold to generate DNA breaks for promoting chromosome exchange. Aim 2 will break new ground in understanding the regulation of eukaryotic topo II, uncovering natural metabolites that control enzyme activity as means to modulate replication, transcription, and chromosome organization processes that are sensitive to DNA topology. Aim 3 will determine how the action of human topo IIβ drives aberrant DNA damaging events and how naturally-occurring mutations may further potentiate this detrimental activity. Our approach is distinguished by a comprehensive blend of biochemical, structural, computational, cell-based, and chemical biology methodologies. Past progress and unpublished findings provide data to establish feasibility for the proposed effort. Our studies will impact multiple fields, from the study of molecular machines and the control of DNA dynamics, to understanding how topoisomerase activity and its regulation support specific physiological needs and promote human reproduction and health.

摘要 DNA拓扑的合理控制对DNA的稳定和流动有重大影响遗传信息。本申请集中于II型拓扑异构酶，调节DNA超级卷曲和移除染色体的分子机器通过催化依赖于ATP的DNA双链转运来实现纠缠又一个。II型拓扑异构酶是维持基因表达的关键，染色体超结构和基因组完整性；它们也是一线药物治疗传染病和癌症的目标。在之前的项目期间，我们对该机制有了几个新的见解，第二类拓扑异构酶的调控和DNA损伤倾向。这些努力开启了提出三个以互补但不相互依赖为中心的新研究机会 II型拓扑异构酶的作用方面将促进基本的生物学知识和治疗干预。目标1试图解释长期悬而未决的关于II型拓扑异构酶如何将依赖于ATP的变构反应与选择性地结合和释放多个DNA片段，并说明负责启动减数分裂重组的系统增选和修饰A 拓扑异构酶支架产生DNA断裂以促进染色体交换。 Aim 2将在理解真核细胞Topo II的调控方面开辟新的天地，发现控制酶活性的天然代谢物作为调节复制、转录和染色体组织过程对 DNA拓扑学。目标3将确定人类TOPO IIβ的行为如何驱动异常 DNA损伤事件以及自然发生的突变如何进一步加强这一点有害的活动。我们的方法的特点是全面融合了生化、结构、计算、细胞和化学生物学方法论。过去的进步和未发表的发现提供了数据，以确定拟议的努力的可行性。我们的研究将影响多个领域，从分子机器的研究到控制了解拓扑异构酶活性及其调控支持特定的生理需求，促进人类生殖和健康。

项目成果

期刊论文数量（47）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

How do type II topoisomerases use ATP hydrolysis to simplify DNA topology beyond equilibrium? Investigating the relaxation reaction of nonsupercoiling type II topoisomerases.

DOI：
10.1016/j.jmb.2008.11.056
发表时间：
2009-02-06
期刊：
JOURNAL OF MOLECULAR BIOLOGY
影响因子：
5.6
作者：
Stuchinskaya, Tanya;Mitchenall, Lesley A.;Schoeffler, Allyn J.;Corbett, Kevin D.;Berger, James M.;Bates, Andrew D.;Maxwell, Anthony
通讯作者：
Maxwell, Anthony

The ancestral role of ATP hydrolysis in type II topoisomerases: prevention of DNA double-strand breaks.