BACKGROUND: Reactive oxygen species, ionizing radiation, and other free radical 
generators initiate the conversion of guanine (G) residues in DNA to 
8-oxoguanine (OG), which is highly mutagenic as it preferentially mispairs with 
adenine (A) during replication. Bacteria counter this threat with a 
multicomponent system that excises the lesion, corrects OG:A mispairs and 
cleanses the nucleotide precursor pool of dOGTP. Although biochemical evidence 
has suggested the existence of base-excision DNA repair proteins specific for OG 
in eukaryotes, little is known about these proteins.
RESULTS: Using substrate-mimetic affinity chromatography followed by a 
mechanism-based covalent trapping procedure, we have isolated a base-excision 
DNA repair protein from Saccharomyces cerevisiae that processes OG opposite 
cytosine (OG:C) but acts only weakly on OG:A. A search of the yeast genome 
database using peptide sequences from the protein identified a gene, OGG1, 
encoding a predicted 43 kDa (376 amino acid) protein, identical to one 
identified independently by complementation cloning. Ogg1 has OG:C-specific 
base-excision DNA repair activity and also intrinsic beta-lyase activity, which 
proceeds through a Schiff base intermediate. Targeted disruption of the OGG1 
gene in yeast revealed a second OG glycosylase/lyase protein, tentatively named 
Ogg2, which differs from Ogg1 in that it preferentially acts on OG:G.
CONCLUSIONS: S. cerevisiae has two OG-specific glycosylase/lyases, which differ 
significantly in their preference for the base opposite the lesion. We suggest 
that one of these, Ogg1, is closely related in overall three-dimensional 
structure to Escherichia coli endonuclease III (endo III), a glycosylase/lyase 
that acts on fragmented and oxidatively damaged pyrimidines. We have recently 
shown that AlkA, a monofunctional DNA glycosylase that acts on alkylated bases, 
is structurally homologous to endo III. We have now identified a shared active 
site motif amongst these three proteins. Using this motif as a protein database 
searching tool, we find that it is present in a number of other base-excision 
DNA repair proteins that process diverse lesions. Thus, we propose the existence 
of a DNA glycosylase superfamily, members of which possess a common fold yet act 
upon remarkably diverse lesions, ranging from UV photoadducts to mismatches to 
alkylated or oxidized bases.