Molecular topology of polycyclic aromatic carcinogens determines DNA adduct conformation: A link to tumorigenic activity

We report below on the solution structures of stereoisomeric "fjord" region trans-anti-benzo[c]phenanthrene-N-2-guanine (designated (BPh)G) adducts po sitioned opposite cytosine within the (C-(BPh)G-C) (G-C-G) sequence context . We observe intercalation of the phenanthrenyl ring with stereoisomer-depe ndent directionality, without disruption of the modified (BPh)G.C base-pair . Intercalation occurs to the 5' side of the modified strand for the 1S ste reoisomeric adduct and to the 3' side for the 1R stereoisomeric adduct, wit h the S and R-trans-isomers related to one another by inversion in a mirror plane at all four chiral carbon atoms on the benzylic ring. Intercalation of the fjord region BPh ring into the helix without disruption of the modif ied base-pair is achieved through buckling of the (BPh)GC base-pair, displa cement of the linkage bond from the plane of the (BPh)G base, adaptation of a chair pucker by the BPh benzylic ring and the propeller-like deviation f rom planarity of the BPh phenanthrenyl ring. It is noteworthy that intercal ation without basepair disruption occurs from the minor groove side for S a nd R-trans-anti BPh-N-2-guanine adducts opposite C, in contrast to our prev ious demonstration of intercalation without modified base-pair disruption f rom the major groove side for S and R-trans-anti BPh-N-6-adenine adducts op posite T. Further, these results on fjord region 1S and 1R-trans-anti (BPh) G adducts positioned opposite C are in striking contrast to earlier researc h with "bay" region benzo[a]pyrene-N-2-guanine (designated (BP)G) adducts p ositioned opposite cytosine, where 10S and 10R-trans-anti stereoisomers wer e positioned with opposite directionality in the minor groove without modif ied base-pair disruption. They also are in contrast to the 10S and 10R-cis- anti stereoisomers of (BP)G adducts opposite C, where the pyrenyl ring is i ntercalated into the helix with directionality, but the modified base and i ts partner on the opposite strand are displaced out of the helix. These res ults are especially significant given the known greater tumorigenic potenti al of fjord region compared to bay region polycyclic aromatic hydrocarbons. The tumorigenic potential has been linked to repair efficiency such that b ay region adducts can be readily repaired while their fjord region counterp arts are refractory to repair. Our structural results propose a link betwee n DNA adduct conformation and repair-dependent mutagenic activity, which co uld ultimately translate into structure-dependent differences in tumorigeni c activities. We propose that the fjord region minor groove-linked BPh-N-2- guanine and major groove-linked BPh-N-6-adenine adducts are refractory to r epair based on our observations that the phenanthrenyl ring intercafates in to the helix without modified base-pair disruption. The helix is therefore minimally perturbed and the phenanthrenyl ring is not available for recogni tion by the repair machinery. By contrast, the bay region BP-N-2-G adducts are susceptible to repair, since the repair machinery can recognize either the pyrenyl ring positioned in the minor groove for the trans-anti groove-a ligned stereoisomers, or the disrupted modified basepair for the cis-anti b ase-displaced intercalated stereoisomers. (C) 2001 Academic Press.