Implications of N7-hydrogen and C8-keto on the base pairing, mutagenic potential and repair of 8-oxo-2′-deoxy-adenosine: Investigation by nucleotide analogues.

[Display omitted] • 8-Br-7-deaza-dA was synthesized and found to resemble the syn -preference of 8-oxo-dA. • Oligodeoxynucleotides incorporating dA, 8-oxo-dA, 7-deaza-dA, 8-Br-dA and 8-Br-7-deaza-dA were synthesized. • The base pairing preferences, mutagenic potentials and repair of 8-oxo-dA and its analogs in duplex DNAs were evaluated. • This study provides an insight into the structure-function relationship of 8-oxo-dA by 8-oxo-dA analogues. Oxidative lesions, such as 8-oxo-dG and 8-oxo-dA, are continuously generated from exposure to reactive oxygen species. While 8-oxo-dG has been extensively studied, 8-oxo-dA has not received as much attention until recently. Herein, we report the synthesis of duplex DNAs incorporating dA, 8-oxo-dA, 7-deaza-dA, 8-Br-dA, and 8-Br-7-deaza-dA, which have different substitutions at 7- and 8-position, for the investigation into the implications of N7-hydrogen and C8-keto on the base pairing preference, mutagenic potential and repair of 8-oxo-dA. Base pairing study suggested that the polar N7-hydrogen and C8-keto of 8-oxo-dA, rather than the syn -preference, might be essential for 8-oxo-dA to form a stable base pair with dG. Insertion and extension studies using KF-exo− and human DNA polymerase β indicated that the efficient dGTP insertion opposite 8-oxo-dA and extension past 8-oxo-dA:dG are contingent upon not only the stable base pair with dG, but also the flexibility of the active site in polymerase. The N7-hydrogen in 8-oxo-dA or C7-hydrogen in 7-deaza-dA and 8-Br-7-deaza-dA was suggested to be important for the recognition by hOGG1, although the excision efficiencies of 7-deaza-dA and 8-Br-7-deaza-dA were much lower than 8-oxo-dA. This study provides an insight into the structure-function relationship of 8-oxo-dA by nucleotide analogues. [ABSTRACT FROM AUTHOR]