Bay-Region Diol Epoxides of Benzo[a]Pyrene are Stealth Poisons of Topoisomerase I

Abstract

Topoisomerase I transiently cleaves one strand of duplex DNA to relieve torsional strain during enzymatic processing events such as transcription and replication. Thus, topoisomerase I is an important target for anti-tumor drugs. We have examined the effects of cis- and trans-opened (+)-7R,8S,9S,10R)- and (−)-(7S,8R,9R,10S)-benzo[a]pyrene 7,8-diol 9,10-epoxide adducts at the exocyclic amino groups of the purine bases at or near a known cleavage site in a 22-mer DNA duplex. The dG adducts lie in the minor groove either upstream or downstream from the modified base, and the dA adducts are intercalated at either side of the modified base. Thus four distinct structural motifs were available for study. The dG adducts inhibit cleavage at the normal site with resultant remote cleavages being observed. In contrast, three of the four dA adducts examined appear to be initially invisible to the enzyme since they allow the normal cleavage to occur, but they prevent subsequent religation and thus act as topoisomerase “stealth poisons”.