Solution structure of a DNA decanter duplex containing the stable 3 ' T center dot G base pair of the pyrimidine(6-4)pyrimidone photoproduct [(6-4) adduct]: Implications for the highly specific 3 ' T -> C transition of the (6-4) adduct

The pyrimidine(6-4)pyrimidone photoproduct [(6-4) adduct] is one of the maj or photoproducts induced by UV irradiation of DNA and occurs at TpT sites. The (6-4) adduct is highly mutagenic and leads most often to a 3' T --> C t ransition with 85% replicating error frequency [LeClerc, J E,, Borden, A. & Lawrence, C, W, (1991) Proc. Natl, Acad, Sci, USA 88, 9685-9689]. To deter mine the origin of the specific 3' T --> C transition of the (6-4) adduct, we have used experimental NMR restraints and molecular dynamics to determin e the solution structure of a (6-4)-lesion DNA decamer duplex that contains a mismatched base pair between the 3' T residue and an opposed G residue. Normal Watson-Crick-type hydrogen bonding is retained at the 5' T of the le sion site. The O2 carbonyl of the 3' T residue forms hydrogen bonds with th e imino and amino protons of the opposed C residue. This potential hydrogen bonding stabilizes the overall helix and restores the highly distorted con formation of the (6-4) adduct to the typical B-form-like DNA structure. Thi s structural feature can explain the marked preference for the insertion of an A residue opposite the 5' T and a G residue opposite the 3' T of the (6 -4) lesion during trans-lesion synthesis. Thus these insertions yield the p redominant 3' T --> C transition.