Abstract
The oxidative DNA damage adduct 8-oxo-7H-adenine (Aoxo) has been shown to incorporate T and G in primer extension reactions catalyzed by a range of polymerases. This paper reports on efforts to characterize the Aoxo · T pairing alignment and the structure at and adjacent to the damage site at the DNA duplex level. The solution structure of an d(G1–C2–A3–T4–G5–T6–G7–T8–A9–C10–G11) · d(C12–G13–T14–A15–C16–Aoxo17–C18–A19–T20–G21–C22) undecanucleotide duplex (designated Aoxo · T 11-mer) was determined by a combination of NMR and molecular dynamics calculations including NOE intensity-based refinements. This sequence forms a right-handed duplex in which all residues are in the anti conformation and all base pairs adopt Watson–Crick pairing alignments. The Aoxo17 residue adopts the 6-amino-8-keto tautomeric arrangement and forms a T6(anti) · Aoxo17(anti) Watson–Crick base pair with the opposing T6 residue on the partner strand. The central d(G5–T6–G7) · d(C16–Aoxo17–C18) three base pair segment of the Aoxo · T 11-mer duplex is very well defined in the relaxation matrix refined structures and its conformation establishes that incorporation of the Aoxo lesion into a DNA duplex has little effect on the DNA structure when paired opposite a thymine residue. These results imply that the recognition of Aoxo · T by the repair machinery is likely to originate in the unusual donor–donor–acceptor hydrogen bonding functionalities at the (NH2-6)–NH7–O8 positions along the major groove edge of the Aoxo lesion.
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