A transversion mutation hypothesis for chemical carcinogenesis by N2-substitution of guanine in DNA

Several carcinogenic aromatic amines and polycyclic hydrocarbons react covalently with the exocyclic amino group (N2) of guanine in DNA. In this study, space-filling molecular models of DNA containing N2-guanyl adducts of 2-acetylaminofluorene (AAF) or benzo[a]pyrene (BP) were constructued. From these models and from available physico-chemical data, it is suggested that the N2 adducts may be easily converted from the normal anti to a syn conformation (base/deoxyribose). This confuguration causes minimal distortion of the DNA model with only a 2--3 A shift in the helical axis of symmetry. Such an alteration may account for the persistence of these adducts in DNA and for the frameshift mutations induced by these carcinogens. Additionally, the syn N2-guanyl configuration places the N-7 and O6 atoms of the modified syn guanine in the base pairing region such that, duration replication, mispairing with N-1 and N2 of an opposite guanine may occur. This would then represent a carcinogen-induced transversion mutation and may lead to neoplastic transformation.