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Abasic Sites Stimulate Double-stranded DNA Cleavage Mediated by Topoisomerase II

1995; Elsevier BV; Volume: 270; Issue: 37 Linguagem: Inglês

10.1074/jbc.270.37.21441

1083-351X

Paul S. Kingma, Anita H. Corbett, Philip Burcham, Lawrence J. Marnett, Neil Osheroff,

Synthesis and bioactivity of alkaloids

Several clinically relevant anticancer drugs induce genomic mutations and cell death by increasing topoisomerase II-mediated DNA breakage. To determine whether endogenous DNA damage also affects this cleavage event, the effects of abasic sites (the most commonly formed spontaneous DNA lesion) on topoisomerase II activity were investigated. The presence of 3 abasic sites/plasmid stimulated enzyme-mediated DNA breakage > 6-fold, primarily by enhancing the forward rate of cleavage. This corresponds to a potency that is > 2000-fold higher than that of the anticancer drug, etoposide. These findings suggest that abasic sites represent endogenous topoisomerase II poisons and imply that anticancer drugs mimic the cleavage-enhancing actions of naturally occurring DNA lesions.