Sequence and Stacking Dependence of 8-Oxoguanine Oxidation:  Comparison of One-Electron vs Singlet Oxygen Mechanisms

• Published in: Journal of the American Chemical Society Vol. 121; no. 40; pp. 9423 - 9428
• Main Authors: Hickerson, Robyn P, Prat, Ferran, Muller, James G, Foote, Christopher S, Burrows, Cynthia J
• Format: Journal Article
• Language: English
• Published: American Chemical Society 13.10.1999
• Subjects: 8-oxoguanine; oligonucleotides
• DOI: 10.1021/ja991929q
• ISSN: 0002-7863

The oxidation of 7,8-dihydro-8-oxoguanine (8-oxoG)-containing oligodeoxynucleotides has been investigated using a variety of oxidants, including one-electron oxidants (Ir(IV), Fe(III), NiCR/KHSO5, and SO4 -•) as well as singlet oxygen, generated both photochemically and thermally. The extents of oxidation in single-stranded and duplex oligodeoxynucleotides are compared, confirming theoretical ionization potentials of 8-oxoG in different sequence contexts in duplex DNA. As with guanine, 8-oxoG residues stacked in a duplex with a 3‘ neighboring G are more readily oxidized by one-electron oxidants than those stacked next to other bases, although the effect of stacking appears to be less pronounced for 8-oxoG than for G. Regardless of sequence, 8-oxoG is always more easily oxidized than the four natural nucleobases, even in the presence of multiple G sequences. Reactions with singlet molecular oxygen, thought to proceed through a cycloaddition mechanism, show little sequence selectivity and a 7-fold higher reactivity with single-stranded compared to duplex 8-oxoG residues. One-electron oxidants, such as Ir(IV) complexes, showed a more modest 3−4-fold higher reactivity with single-stranded DNA. In contrast, the Schiff base complex [NiCR]2+, used in conjunction with a strong oxidant, KHSO5, shows a 2-fold preference for oxidation of duplex vs single-stranded 8-oxoG, perhaps because of the high driving force and the possibility for competing G oxidation to equilibrate to 8-oxoG oxidation via hole transfer. Overall, these results point to subtle mechanistic differences in one-electron oxidation but a major distinction between one-electron and 1O2-mediated oxidation. Furthermore, they suggest an important role for 8-oxoG, not only as a product of oxidative DNA damage but also as a substrate for further oxidation.