Understanding and exploiting DNA topoisomerases in cancer biology

了解和利用癌症生物学中的 DNA 拓扑异构酶

• 批准号: 10473793
• 负责人: JAMES M BERGER
• 金额: $ 88.51万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10473793
• 关键词: Amino Acid Sequence; Antineoplastic Agents; Biochemical; Biology; Cancer Biology; Cancer Etiology; Cells; Chemicals; Chromatin; Chromosomal Instability; Chromosomes; Citric Acid Cycle; DNA; DNA Damage; DNA Topoisomerases; Drug Targeting; Enzymes; Eukaryotic DNA Topoisomerases II; Genetic; Goals; Human Chromosomes; Malignant Neoplasms; Methodology; Molecular Machines; Outcome; Pharmaceutical Preparations; Play; Proteins; Research; Role; Site; Specificity; Superhelical DNA; Topoisomerase; Topoisomerase II; Variant; Work; base; cancer cell; cancer therapy; genetic information; genome integrity; improved; innovation; mutant

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 DNA 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 play a frontline role in cancer biology as factors that can both maintain and disrupt genome integrity; they are also demonstrated drug targets for treating cancer. Our past research on eukaryotic topoisomerase II (topo II) has opened up new research avenues for understanding cancer etiology and improving cancer treatment. The present application will deliver groundbreaking solutions to key problems in the field, including how certain classes of anti-topo II drugs act on the enzyme, how topo II is localized to key sites of action where it resolves potentially deleterious chromosomal topologies, and how aberrant topo II activity can promote DNA damage and genetic instability. We will also investigate innovative concepts and highly significant lines of inquiry raised by our new findings, such as how metabolites produced by the TCA cycle control topo II function. Our approach is distinguished by a comprehensive blend of biochemical, structural, computational, cell-based, and chemical biology methodologies. High-impact outcomes will include defining how topo II appropriately localizes with chromatin and partner proteins to mitigate its natural DNA-damaging potential, establishing how the specificity of anti-topo II agents can be improved to enhance their utility in cancer treatment, and revealing the potential for natural amino-acid sequence variation in type II topoisomerases to destabilize human chromosomes and act as cancer drivers. Past progress and unpublished findings establish the feasibility of our planned goals.

抽象的 DNA拓扑结构的适当控制对DNA的稳定性和流动性有重大影响 遗传信息。本申请重点关注 II 型 DNA 拓扑异构酶， 调节 DNA 超螺旋并去除染色体的分子机器 通过催化一个 DNA 双链体的 ATP 依赖性运输来实现缠结 其他。 II 型拓扑异构酶在癌症生物学中发挥着前沿作用，作为可以 维持和破坏基因组完整性；它们也被证明是药物靶点 治疗癌症。 我们过去对真核拓扑异构酶II（topo II）的研究开辟了新的研究领域 了解癌症病因和改善癌症治疗的途径。现在的 应用程序将为该领域的关键问题提供突破性的解决方案，包括如何 某些类别的抗拓扑 II 药物作用于酶，拓扑 II 如何定位到关键位点 它解决潜在有害染色体拓扑的作用，以及如何解决 异常的拓扑 II 活性会促进 DNA 损伤和遗传不稳定。我们也会 研究我们的新产品提出的创新概念和非常重要的问题 研究结果，例如 TCA 循环产生的代谢物如何控制拓扑 II 功能。 我们的方法以生化、结构、 计算、基于细胞和化学生物学方法。高影响力成果 将包括定义拓扑 II 如何与染色质和伴侣蛋白适当定位 为了减轻其自然 DNA 损伤的潜力，确定反拓扑的特异性如何 可以改进 II 剂以增强其在癌症治疗中的效用，并揭示 II 型拓扑异构酶中天然氨基酸序列变异可能导致不稳定 人类染色体并充当癌症驱动因素。过去的进展和未发表的发现 确定我们计划目标的可行性。