Adduct-induced base-shifts: a mechanism by which the adducts of bulky carcinogens might induce mutations.

Most carcinogens have been shown to be mutagens, and DNA adducts are formed when mutagenic/carcinogenic substances react with DNA. It is generally believed these adducts (or their derivatives) induce misreplication events that result in mutations. Many of the more potently mutagenic substances are bulky and three-dimensionally complex, such as the polycyclic aromatic hydrocarbons, aromatic amines, and aflatoxins; little is known about the mechanisms by which they induce mutations. Several theories exist and herein an additional mechanism is proposed by which bulky adducts might induce mutations at GC base pairs. Molecular modeling in conjunction with molecular mechanical calculation is used to assess if the mutagen/carcinogen moiety of the adduct might be able to shift the position of the base moiety of the adduct in such a way that misreplication events might be facilitated. This mechanism is referred to as adduct-induced base-shift, and two classes appeared possible; adduct-induced base-wobble and adduct-induced base-rotation. The latter has been proposed previously. By adduct-induced, base-wobble, the mutagen/carcinogen moiety of the adduct induces a shift in the position of the base moiety of the adduct with respect to the helix axis, which might facilitate mispairing events that are reminisent of non-Watson/Crick pairing that occurs at the wobble base of tRNA during translation. For example, in some guanine adducts, the guanine appears more thymine-like, which might facilitate G.A mispairing and thereby ultimately GC to TA transversion mutations. Adduct-induced base-rotation involves the rotation of the adducted base from the anti to the syn conformation and a variety of mispairing events might result.