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Structure of DNA Polymerase β with the Mutagenic DNA Lesion 8-Oxodeoxyguanine Reveals Structural Insights into Its Coding Potential
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Oxidative damage to DNA generates 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG). During DNA replication and repair synthesis, 8-oxodG can pair with cytosine or adenine. The ability to accurately replicate through this lesion depends on the DNA polymerase. We report the first structure of a polymerase with a promutagenic DNA lesion, 8-oxodG, in the confines of its active site. The modified guanine residue is in an anti conformation and forms Watson-Crick hydrogen bonds with an incoming dCTP. To accommodate the oxygen at C8, the 5'-phosphate backbone of the templating nucleotide flips 180 degrees. Thus, the flexibility of the template sugar-phosphate backbone near the polymerase active site is one parameter that influences the anti-syn equilibrium of 8-oxodG. Our results provide insights into the mechanisms employed by polymerases to select the complementary dNTP.
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“However, Pol  avoids this inaccurate reaction by flipping the 5Ј-phosphate backbone of the templating nucleotide 180°, relieving a steric clash with the oxygen at C-8 and allowing non-mutagenic pairing of incoming dCTP with 8-oxy-dG in the Watson-Crick anti conformation ( 46).”
From DNA Replication Fidelity (2004) · cites this paper as [46]
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Metadata
- Authors
- Krahn, J. M., Beard, W. A., Miller, H., Grollman, A. P., & Wilson, S. H.
- Affiliations
- National Institutes of Health (US)
- State University of New York (US)
- Corresponding author
- Wilson, Samuel H
- Venue
- Structure
- Publisher
- Elsevier BV
- Published
- 2003-01
- Volume
- 11
- Issue
- 1
- Pages
- 121-127
- ISSN
- 0969-2126 (ISSN-L)
- OpenAlex
- W2082963155
- Cited by
- 138
- References
- 46
- Citations by year
- 2025: 2 · 2022: 4 · 2021: 7 · 2020: 2 · 2019: 2 · 2018: 6 · 2017: 5 · 2016: 9 · 2015: 3 · 2014: 5 · 2013: 8 · 2012: 7
- FWCI
- 4.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Structure (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (CA 47995, P01CA047995)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
- Keywords
- DNA polymerase beta, oxidative DNA damage, polymerase active site, Watson-Crick hydrogen bonding, DNA replication, DNA repair synthesis, crystal structure
- MeSH terms
- Binding Sites, Deoxyadenine Nucleotides, DNA Damage, DNA Repair, DNA Replication, Guanine, Humans, Models, Molecular, Nucleic Acid Conformation, Molecular Structure, Protein Structure, Tertiary, DNA Polymerase beta
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