DNA Lesions as Endogenous Topoisomerase Poisons

拓扑异构酶II是一种重要的酶，它可以松弛DNA，去除基因中的结和缠结 材料通过一个完整的双螺旋通过它在 分开的DMA段。然而，由于拓扑异构酶II必须按顺序产生双链DMA断裂 为了履行其催化功能，该酶还对基因组完整性构成了内在威胁。超越它的 重要的细胞功能，拓扑异构酶II是一些最有效的抗癌药物的主要靶点 目前在临床上使用。这些药物通过增加共价拓扑异构酶11-裂解的DMA水平起作用 酶催化循环中正常但转瞬即逝的中间体。当 由此产生的酶相关的DMA断裂以高浓度的形式存在，它们会产生突变， 染色体易位，并触发细胞死亡途径。针对II型的抗癌药物 酶被称为拓扑异构酶II毒药，因为它们将这种重要的酶转化为一种有效的 使基因组碎裂的生理性毒素。尽管拓扑异构酶II是最重要的 作为癌症治疗的靶点，有令人信服的证据表明，这种酶造成的DNA断裂也 引发特定类型的白血病。这表明拓扑异构酶11靶向的药物可能代表了 诱导DNA重组、突变或细胞死亡的外源细胞成分的对应物 小路。以前的研究(许多来自皮亚板)表明，最常见的形成于 DNA损伤和其他生理性DNA损伤刺激拓扑异构酶11介导的DNA裂解 这种药效比广泛使用的抗癌药物依托泊苷要高得多。因此， 这项提议的最终目标是进一步确定拓扑异构酶II和DNA损伤之间的相互作用 并确定DNA损伤在细胞中是否作为内源性拓扑异构酶II毒物发挥作用。这个 这项研究的模型将是人类拓扑异构酶llpha和beta，以及培养的哺乳动物细胞系。 相关性：拓扑异构酶II是一些最重要的抗癌药物临床使用的靶点。 然而，也有证据表明，这种酶会触发染色体断裂，从而引发白血病。这个 目前的提议验证了DNA损伤作为抗癌药物的内源性对应物的假设 并可能参与启动拓扑异构酶11介导的白血病染色体易位。

Topoisomerase II is an essential enzyme that relaxes DMAand removes knots and tangles from the genetic material by passing an intact double helix through a transient double-stranded break that it generates in a separate DMAsegment. However, since topoisomerase II must create double-stranded DMA breaks in order to carry out its catalytic functions, the enzyme also poses an intrinsic threat to genomic integrity. Beyond its critical cellular functions, topoisomerase II is the primary target for some of the most active anticancer drugs currently in clinical use.These drugs act by increasing levels of covalent topoisomerase ll-cleaved DMA complexes that are normal, but fleeting, intermediates in the catalytic cycle of the enzyme. When the resulting enzyme-associated DMA breaks are present in high concentrations, they generate mutations, chromosomal translocations, and trigger cell death pathways. Anticancer drugs targeted to the type II enzyme are referred to as topoisomerase II poisons because they convert this essential enzyme to a potent physiological toxin that fragments the genome. Although topoisomerase II is one of the most important targets for cancer treatment, there is compelling evidence that DNA breaks created by the enzyme also trigger specific types of leukemia. This suggests that topoisomerase ll-targeted drugs may represent exogenous counterparts of cellular components that induce DNA recombination, mutagenesis, or cell death pathways. Previous studies (many from the Pi'slab)indicate that abasic sites, the most commonly formed lesion in DNA, and other physiological DNA lesions stimulate topoisomerase ll-mediated DNA cleavage with a potency that is considerably higher than that of the widely prescribed anticancer drug etoposide. Thus, the ultimate goals of this proposal are to further define interactions between topoisomerase II and DNA damage and to determine whether DNA lesions function in cells as endogenous topoisomerase II poisons. The models for this study will be human topoisomerase llalpha and beta, and cultured mammalian cell lines. RELEVANCE: Topoisomerase II is the target for some of the most important anticancer drugs in clinicaluse. However, there is also evidence that the enzyme triggers chromosomal breaks that trigger leukemia. The current proposal tests the hypothesis that DNA lesions act as endogenous counterparts of anticancer drugs and may be involved in initiating topoisomerase ll-mediated leukemic chromosomal translocations.