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The Fidelity of Human DNA Polymerase γ with and without Exonucleolytic Proofreading and the p55 Accessory Subunit
Open accessAbstract
Mutations in human mitochondrial DNA influence aging, induce severe neuromuscular pathologies, cause maternally inherited metabolic diseases, and suppress apoptosis. Since the genetic stability of mitochondrial DNA depends on the accuracy of DNA polymerase gamma (pol gamma), we investigated the fidelity of DNA synthesis by human pol gamma. Comparison of the wild-type 140-kDa catalytic subunit to its exonuclease-deficient derivative indicates pol gamma has high base substitution fidelity that results from high nucleotide selectivity and exonucleolytic proofreading. pol gamma is also relatively accurate for single-base additions and deletions in non-iterated and short repetitive sequences. However, when copying homopolymeric sequences longer than four nucleotides, pol gamma has low frameshift fidelity and also generates base substitutions inferred to result from a primer dislocation mechanism. The ability of pol gamma both to make and to proofread dislocation intermediates is the first such evidence for a family A polymerase. Including the p55 accessory subunit, which confers processivity to the pol gamma catalytic subunit, decreases frameshift and base substitution fidelity. Kinetic analyses indicate that p55 promotes extension of mismatched termini to lower the fidelity. These data suggest that homopolymeric runs in mitochondrial DNA may be particularly prone to frameshift mutation in vivo due to replication errors by pol gamma.
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“This explains why the insertion/ deletion error rates of most polymerases increase with increasing repeat sequence length and why even proofreading-proficient replicative DNA polymerases with very high base substitution fidelity have low single base deletion fidelity (e.g.Fig. 1, bottom) when copying long homopolymeric sequences (e.g.Refs.55 and 60 and references therein).”
From DNA Replication Fidelity (2004) · cites this paper as [60]
Experimental — accuracy not yet measuredIn the citing paper
“The intrinsic 3′ → 5′ exonuclease activity of Pol γ improves replication fidelity at least 20-fold (Longley et al., 2001).”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Longley et al., 2001
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“High fidelity is due to high nucleotide selectivity and exonucleolytic proofreading.”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Longley et al., 2001
In the citing paper
“The human catalytic subunit of Pol γ has high base substitution fidelity over short repeat sequences (< 3 nucleotides), as a misinsertion event only occurs approximately once in every 500,000 base pairs synthesized (Longley et al., 2001).”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Longley et al., 2001
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Metadata
- Authors
- Longley, M. J., Nguyen, D., Kunkel, T. A., & Copeland, W. C.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Copeland, William C.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2001-10
- Volume
- 276
- Issue
- 42
- Pages
- 38555-38562
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1998344938
- Cited by
- 270
- References
- 77
- Citations by year
- 2026: 16 · 2025: 10 · 2024: 6 · 2023: 4 · 2022: 6 · 2021: 14 · 2020: 21 · 2019: 4 · 2018: 5 · 2017: 9 · 2016: 8 · 2015: 13 · 2014: 4 · 2013: 7 · 2012: 10
- FWCI
- 5.32
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Keywords
- DNA polymerase gamma, mitochondrial DNA, replication fidelity, exonuclease proofreading, frameshift mutation, mismatch extension, nucleotide selectivity, mitochondrial DNA mutations
- MeSH terms
- DNA Polymerase gamma, Catalysis, DNA-Directed DNA Polymerase, DNA Repair, DNA, Mitochondrial, Humans, Kinetics, Mutation, Phenotype, Recombinant Proteins, Repetitive Sequences, Nucleic Acid, Mutagenesis, Frameshift Mutation, Gene Deletion, Base Pair Mismatch
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