Topoisomerase I transiently cleaves one strand of duplex DNA to relieve tor
sional strain during enzymatic processing events such as transcription and
replication. Thus, topoisomerase I is an important target for anti-tumor dr
ugs. We have examined the effects of cis- and trans-opened (+)-(7R,8S,9S, 1
0R)- 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 inter
calated at either side of the modified base. Thus four distinct structural
motifs were available for study. The dG adducts inhibit cleavage at the nor
mal site with resultant remote cleavages being observed. In contrast, three
of the four dA adducts examined appear to be initially invisible to the en
zyme since they allow the normal cleavage to occur, but they prevent subseq
uent religation and thus act as topoisomerase "stealth poisons".