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Structural Studies of the Ionizing Radiation Adduct 7,8‐Dihydro‐8‐oxoadenine (A oxo ) Positioned Opposite Thymine in a DNA Duplex
Author(s) -
Chen Huifen,
Johnson Francis,
Grollman Arthur P.,
Patel Dinshaw J.
Publication year - 1996
Publication title -
magnetic resonance in chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.483
H-Index - 72
eISSN - 1097-458X
pISSN - 0749-1581
DOI - 10.1002/(sici)1097-458x(199612)34:13<s23::aid-omr16>3.0.co;2-v
Subject(s) - chemistry , thymine , ionizing radiation , adduct , duplex (building) , dna , non ionizing radiation , radiation , irradiation , organic chemistry , optics , biochemistry , nuclear physics , physics
The oxidative DNA damage adduct 8‐oxo‐7 H ‐adenine (A oxo ) 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 A oxo · 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–A oxo 17–C18–A19–T20–G21–C22) undecanucleotide duplex (designated A oxo · 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 A oxo 17 residue adopts the 6‐amino‐8‐keto tautomeric arrangement and forms a T6( anti ) · A oxo 17( anti ) Watson–Crick base pair with the opposing T6 residue on the partner strand. The central d(G5–T6–G7) · d(C16–A oxo 17–C18) three base pair segment of the A oxo · T 11‐mer duplex is very well defined in the relaxation matrix refined structures and its conformation establishes that incorporation of the A oxo 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 A oxo · T by the repair machinery is likely to originate in the unusual donor–donor–acceptor hydrogen bonding functionalities at the (NH 2 ‐6)–NH7–O8 positions along the major groove edge of the A oxo lesion.