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Fundamental Biological Processes Under Torsion

扭转下的基本生物过程

基本信息

批准号：
10621261
负责人：
MICHELLE D. WANG
金额：
$ 29.98万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10621261
关键词：
Address Antineoplastic Agents Automobile Driving Benchmarking Binding Sites Biological Biological Assay Biological Process Chromatin Chromatin Fiber Complex Creativeness DNA DNA Damage DNA Structure DNA biosynthesis DNA replication fork Data Daughter Development Drug Targeting Effectiveness Excision Fostering Future Generations Genetic Transcription Genomic Instability Health Histone H1 Human Human Genome Investigation Magnetism Maps Measurement Measures Mechanics Methods Mission Molecular Monitor Nature Nucleosomes Pharmaceutical Preparations Play Process Property Regulation Relaxation Research Resolution Role Rotation Specificity Stress Superhelical DNA Techniques Therapeutic Agents Time Topoisomerase Topoisomerase Interaction Torque Torsion Type I DNA Topoisomerases United States National Institutes of Health Work cancer therapy daughter strand ds-DNA genome-wide genome-wide analysis human disease improved innovation insight mechanical properties novel novel therapeutics optic trap optical traps preference side effect single molecule

项目摘要

Project Summary The helical nature of double stranded DNA (dsDNA) innately promotes the generation of torsional stress during essential processes such as replication and transcription. In particular, replication will inevitably generate DNA supercoiling which may braid or intertwine daughter DNA strands, creating precatenanes. Such intertwining, if not properly resolved, results in DNA damage, genome instability, and replication arrest. Though critical to cellular viability, these problems are highly complex, posing significant barriers to experimentation. Thus our mechanistic understanding has remained conspicuously limited. The work proposed here aims to address the role that the torsional mechanical properties of chromatin play in determining the formation and resolution of topological impasses, and in turn, the implications this has for topoisomerase function. Aim 1 will establish methods to create, benchmark, and manipulate both single and braided chromatin substrates. Since little is known about how topoisomerases interact with chromatin substrates, Aim 2 will develop a novel assay to monitor topoisomerase activity, in real time, and directly apply this approach to examine different topoisomerases to determine their effectiveness in supercoiling removal and substrate preferences. This will also allow investigation into how therapeutic agents impact topoisomerase activity. Finally, Aim 3 will examine broadly replication generated torsion and topoisomerase binding sites genome wide. To pursue these aims we will leverage state-of-the-art single molecule and genome wide techniques – including established approaches and novel assays. The proposed research will demonstrate the broad role of the intrinsic mechanical properties of chromatin in fundamental biological processes and will have far-reaching impacts into the treatment of human disease and the development of novel therapeutic agents.

项目摘要双链DNA（dsDNA）的螺旋性质先天地促进了DNA的产生。在复制和转录等基本过程中的扭转应力。特别是，复制过程中不可避免地会产生DNA超螺旋，这种超螺旋可能会编织或插入子代 DNA链，产生前环烷烃。这种缠绕，如果没有得到适当的解决，损伤、基因组不稳定性和复制停滞。虽然对细胞活力至关重要，但这些问题非常复杂，给实验带来了重大障碍。因此我们的机械的理解仍然明显有限。这里提出的工作旨在为了解决染色质的扭转机械特性在决定细胞的结构中所起的作用，拓扑僵局的形成和解决，反过来，这对拓扑异构酶功能目标1将建立创建、基准测试和操作的方法单个和编织染色质底物。由于我们对拓扑异构酶与染色质底物相互作用，Aim 2将开发一种新的检测拓扑异构酶的方法活动，在真实的时间，并直接应用这种方法来检查不同的拓扑异构酶，确定它们在去除超螺旋和基底偏好方面的有效性。这也将允许研究治疗剂如何影响拓扑异构酶活性。最后，Aim 3将研究广泛复制产生的扭转和拓扑异构酶结合位点的基因组范围。为了实现这些目标，我们将利用最先进的单分子和全基因组技术-包括已建立的方法和新的测定。拟议的研究将证明了染色质的内在机械特性在基础研究中的广泛作用。将对人类疾病的治疗产生深远的影响以及新型治疗剂的开发。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Topoisomerase II and etoposide - a tangled tale.

DOI：
10.1038/s41589-022-01236-8
发表时间：
2023-05
期刊：
NATURE CHEMICAL BIOLOGY
影响因子：
14.8
作者：
Le, Tung T.;Wang, Michelle D.
通讯作者：
Wang, Michelle D.

Resonator nanophotonic standing-wave array trap for single-molecule manipulation and measurement.

DOI：
10.1038/s41467-021-27709-3
发表时间：
2022-01-10
期刊：
Nature communications
影响因子：
16.6
作者：
Ye F;Inman JT;Hong Y;Hall PM;Wang MD
通讯作者：
Wang MD

Ruler of Life.

生命的主宰。

DOI：
10.1038/s41567-021-01300-5
发表时间：
2021
期刊：
Nature physics
影响因子：
19.6
作者：
Wang,MichelleD
通讯作者：
Wang,MichelleD

Angular Optical Trapping to Directly Measure DNA Torsional Mechanics.

角度光学捕获直接测量 DNA 扭转力学。

DOI：
10.1007/978-1-0716-2229-2_4
发表时间：
2022
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
0
作者：
Gao,Xiang;Inman,JamesT;Wang,MichelleD
通讯作者：
Wang,MichelleD

Physics meets biology: The joining of two forces to further our understanding of cellular function.

物理学与生物学的结合：两种力量的结合进一步加深了我们对细胞功能的理解。

DOI：
10.1016/j.molcel.2021.07.009
发表时间：
2021
期刊：
Molecular cell
影响因子：
16
作者：
Wang,MichelleD;Nicodemi,Mario;Dekker,NynkeH;Gregor,Thomas;Holcman,David;vanOijen,AntoineM;Manley,Suliana
通讯作者：
Manley,Suliana