Understanding and exploiting DNA topoisomerases in cancer biology

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。本申请的重点是II型DNA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型拓扑异构酶作为一种因子在癌症生物学中发挥着重要的作用 两者都维持和破坏基因组的完整性；它们也被证明是治疗 治疗癌症。 我们过去对真核细胞拓扑异构酶II(Topo II)的研究开辟了新的研究领域 了解癌症病因和改进癌症治疗的途径。现在 应用程序将为该领域的关键问题提供开创性的解决方案，包括如何 某些类别的抗Topo II药物作用于该酶，Topo II如何定位于关键部位 它在哪里解决了潜在的有害染色体拓扑，以及如何 Topo II活性异常可促进DNA损伤和遗传不稳定性。我们还将 调查由我们的新产品提出的创新概念和高度重要的调查路线 研究结果，如三氯乙酸循环产生的代谢物如何控制TOPO II的功能。 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。高影响力的成果 将包括定义Topo II如何与染色质和配对蛋白适当定位 为了减轻其天然的DNA损伤潜力，确立了抗TOPO的特异性 可以改进II类药物以增强其在癌症治疗中的效用，并揭示 II型拓扑异构酶的天然氨基酸序列变异可能导致不稳定 人类的染色体，并作为癌症的驱动力。过去的进展和未发表的研究结果 确定我们计划目标的可行性。

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.