Structural basis for recognition and repair of the endogenous mutagen 8-oxoguanine in DNA.
Spontaneous oxidation of guanine residues in DNA generates 8-oxoguanine (oxoG). By mispairing with adenine during replication, oxoG gives rise to a G x C --> T x A 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 oxoG x C 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 oxoG x C-containing DNA at 2.1 A 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 promutator by relaxing the specificity of the enzyme for the base opposite oxoG.
Bruner
S D
SD
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
Norman
D P
DP
Verdine
G L
GL
D000595:Amino Acid Sequence; D002384:Catalysis; D020134:Catalytic Domain; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D003596:Cytosine / Q000737:chemistry; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D004260:DNA Repair; D043382:DNA-Formamidopyrimidine Glycosylase; D004926:Escherichia coli; D029968:Escherichia coli Proteins; D006147:Guanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009153:Mutagens / Q000737:chemistry* / Q000378:metabolism; D009154:Mutation; D009699:N-Glycosyl Hydrolases / Q000737:chemistry*; D009690:Nucleic Acid Conformation; D011485:Protein Binding; D011487:Protein Conformation; D016415:Sequence Alignment; D013329:Structure-Activity Relationship
D029968:Escherichia coli Proteins; D009153:Mutagens; D006147:Guanine; C064582:8-oxyguanine; D003596:Cytosine; D004247:DNA; D009699:N-Glycosyl Hydrolases; D043382:DNA-Formamidopyrimidine Glycosylase; C468610:DNA-formamidopyrimidine glycosylase, E coli