DNA Lesions as Endogenous Topoisomerase Poisons

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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.