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. 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.
Kingma
P S
PS
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA.
Corbett
A H
AH
Burcham
P C
PC
Marnett
L J
LJ
Osheroff
N
N
D000818:Animals; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000302:isolation & purification / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000196:embryology; D004625:Embryo, Nonmammalian / Q000201:enzymology; D007700:Kinetics; D009690:Nucleic Acid Conformation; D010957:Plasmids; D013379:Substrate Specificity
D004247:DNA; D004250:DNA Topoisomerases, Type II