ABASIC SITES STIMULATE DOUBLE-STRANDED DNA CLEAVAGE MEDIATED BY TOPOISOMERASE-II - DNA LESIONS AS ENDOGENOUS TOPOISOMERASE-II POISONS

Several clinically relevant anticancer drugs induce genomic mutations and cell death by increasing topoisomerase II-mediated DNA breakage. T o determine whether endogenous DNA damage also affects this cleavage e vent, the effects of abasic sites (the most commonly formed spontaneou s DNA lesion) on topoisomer ase II activity were investigated. The pre sence of 3 abasic sites/plasmid stimulated enzyme-mediated DNA breakag e >6-fold, primarily by enhancing the forward rate of cleavage, This c orresponds to a potency that is >2000-fold higher than that of the ant icancer drug, etoposide. These findings suggest that abasic sites repr esent endogenous topoisomerase II poisons and imply that anticancer dr ugs mimic the cleavage-enhancing actions of naturally occurring DNA le sions.