Structural basis for recognition and repair of the endogenous mutagen 8-oxoguanine in DNA

Spontaneous oxidation of guanine residues in DNA generates 8-oxoguanine (ox oG), By mispairing with adenine during replication, oxoG gives rise to a G. C --> T.A transversion, a frequent somatic mutation in human cancers. The d edicated repair pathway for oxoG centres on 8-oxoguanine DNA glycosylase (h 0GG1), an enzyme that recognizes oxoG.C base pairs, catalysing expulsion of the oxoG and cleavage of the DNA backbone. Here we report the X-ray struct ure of the catalytic core of h0GG1 bound to oxoG.C-containing DNA at 2.1 An gstrom resolution. The structure reveals the mechanistic basis for the reco gnition and catalytic excision of DNA damage by h0GG1 and by other members of the enzyme superfamily to which it belongs. The structure also provides a rationale for the biochemical effects of inactivating mutations and polym orphisms in hOGG1. One known mutation, R154H, converts h0GG1 to a promutato r by relaxing the specificity of the enzyme for the base opposite oxoG.