A Reexamination of the Nucleotide Incorporation Fidelity of DNA Polymerases
Abstract
Intensive study has been devoted to understanding the kinetic and structural bases underlying the exceptionally high fidelity (low error frequencies) of the typical DNA polymerase. Commonly proposed explanations have included (i) the concept of fidelity check points, in which the correctness of a nascent base pair match is tested at multiple points along the reaction pathway, and (ii) an induced-fit fidelity enhancement mechanism based on a rate-limiting, substrate-induced conformational change. In this article, we consider the evidence and theoretical framework for the involvement of such mechanisms in fidelity enhancement. We suggest that a "simplified" model, in which fidelity is derived fundamentally from differential substrate binding at the transition state of a rate-limiting chemical step, is consistent with known data and sufficient to explain the substrate selectivity of these enzymes.
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Kinetic studies have established that fidelity depends on differences in the binding affinities and insertion rates of incorrect versus correct dNTPs.
“Kinetic studies (reviewed in Refs.15,19,[33][34][35][36] have established that fidelity depends on differences in the binding affinities and insertion rates of incorrect versus correct dNTPs.”
From DNA Replication Fidelity (2004) · cites this paper as [35]
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- Authors
- Showalter, A. K., & Tsai, M.-D.
- Affiliations
- The Ohio State University (US)
- ORCID
- Tsai, Ming-Daw
- Venue
- Biochemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2002-08-01
- Volume
- 41
- Issue
- 34
- Pages
- 10571-10576
- ISSN
- 0006-2960 (ISSN-L)
- 1520-4995
- OpenAlex
- W2114997522
- Cited by
- 142
- References
- 40
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 3 · 2023: 6 · 2022: 2 · 2021: 3 · 2020: 3 · 2019: 2 · 2018: 6 · 2017: 5 · 2016: 3 · 2015: 6 · 2014: 7 · 2013: 2 · 2012: 4
- FWCI
- 0.80
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (GM 43268, R01GM043268)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Reaction Mechanisms
- Keywords
- DNA polymerase, induced fit, substrate binding, transition state, rate-determining step, substrate specificity, error rate, conformational change
- MeSH terms
- DNA-Directed DNA Polymerase, DNA Replication, Kinetics, Models, Biological, Nucleotides, Protein Binding, Protein Conformation, Substrate Specificity, Thermodynamics
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