1. Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA

Correspondence to: Gregory L. Verdine Correspondence and requests for materials should be addressed to G.L.V. (e-mail: Email: verdine@chemistry.harvard.edu). Atomic coordinates have been deposited in the PDB under access code 1EBM and can be downloaded from http://glviris.harvard.edu/research/HOGG1.

Abstract

Spontaneous oxidation of guanine residues in DNA generates 8-oxoguanine (oxoG). By mispairing with adenine during replication, oxoG gives rise to a GC TA transversion, a frequent somatic mutation in human cancers. The dedicated repair pathway for oxoG centres on 8-oxoguanine DNA glycosylase (hOGG1), an enzyme that recognizes oxoGC base pairs, catalysing expulsion of the oxoG and cleavage of the DNA backbone. Here we report the X-ray structure of the catalytic core of hOGG1 bound to oxoGC-containing DNA at 2.1 Å resolution. The structure reveals the mechanistic basis for the recognition and catalytic excision of DNA damage by hOGG1 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 polymorphisms in hOGG1. One known mutation, R154H, converts hOGG1 to a pro-mutator by relaxing the specificity of the enzyme for the base opposite oxoG.