Cited by 138DNA and Nucleic Acid ChemistryDNA Repair MechanismsEnzyme Structure and Function

Structure of DNA Polymerase β with the Mutagenic DNA Lesion 8-Oxodeoxyguanine Reveals Structural Insights into Its Coding Potential

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Krahn, Joseph M, Beard, William A, Miller, Holly, Grollman, Arthur P, Wilson, Samuel H·2003·Structure

Abstract

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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Crossref · 10.1016/s0969-2126(02)00930-9

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  • Pol β avoids this inaccurate reaction by flipping the 5'-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.

    “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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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
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
  • Physical Sciences › Materials Science › Materials Chemistry › 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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