Structural basis for recognition and repair of the endogenous mutagen 8-oxoguanine in DNA
Abstract
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.
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Structures of DNA in complex with OGG1 exist in a catalytically active form for 8oxoG that is adjacent to guanine only in the 5'-position in -AGGT- sequences.
“In fact, the structures of DNA in complex with N-glycosylase/DNA lyase (OGG1), which is a base-excision repair enzyme for 8oxoG, exist in a catalytically active form for 8oxoG that is adjacent to guanine only in the 5’-position in -AGGT- sequences (S12 Fig) [40,48–51].”
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- Authors
- Bruner, S. D., Norman, D. P. G., & Verdine, G. L.
- Affiliations
- Harvard University (US)
- Corresponding author
- Verdine, Gregory L.
- Venue
- Nature
- Published
- 2000-02
- Volume
- 403
- Issue
- 6772
- Pages
- 859-866
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1833739857
- Cited by
- 972
- References
- 47
- Citations by year
- 2026: 22 · 2025: 31 · 2024: 30 · 2023: 25 · 2022: 34 · 2021: 34 · 2020: 30 · 2019: 28 · 2018: 33 · 2017: 29 · 2016: 28 · 2015: 39 · 2014: 41 · 2013: 44 · 2012: 41
- FWCI
- 18.65
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- 8-oxoguanine, OGG1, DNA glycosylase, DNA repair, base excision repair, transversions, guanine oxidation, DNA damage recognition, enzyme mechanism, X-ray crystal structure
- MeSH terms
- Amino Acid Sequence, Catalysis, Cloning, Molecular, Cytosine, DNA, DNA Repair, Escherichia coli, Guanine, Humans, Models, Molecular, Molecular Sequence Data, Mutagens, Mutation, Nucleic Acid Conformation, N-Glycosyl Hydrolases, Protein Binding, Protein Conformation, Structure-Activity Relationship, Sequence Alignment, Crystallography, X-Ray, Catalytic Domain, Escherichia coli Proteins, DNA-Formamidopyrimidine Glycosylase
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