The DOI matches its Crossref record; 77 of the 77 references it cites were found in a registry or an index.
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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In the citing paper
“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
In the citing paper
“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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Citations
Cites
Sequence and organization of the human mitochondrial genome
Anderson, S., Bankier, A. T., Barrell, B. G., de Bruijn, M. H. L., Coulson, A. R., Drouin, J., Eperon, I. C., Nierlich, D. P., Roe, B. A., Sanger, F., et al. (1981) · Nature · doi:10.1038/290457a0 · Cited by 9,740
Rapid evolution of animal mitochondrial DNA
Brown, W. M., George, M., & Wilson, A. C. (1979) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.76.4.1967 · Cited by 3,439
Mitochondrial diseases in man and mouse
Wallace, D. C. (1999) · Science · doi:10.1126/science.283.5407.1482 · Cited by 3,060
Mitochondrial DNA sequences of primates: tempo and mode of evolution
Brown, W. M., Prager, E. M., Wang, A., & Wilson, A. C. (1982) · Journal of Molecular Evolution · doi:10.1007/bf01734101 · Cited by 1,554
Frameshift Mutations and the Genetic Code
Streisinger, G., Okada, Y., Emrich, J., Newton, J., Tsugita, A., Terzaghi, E., & Inouye, M. (1966) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.1966.031.01.014 · Cited by 1,400
Diseases of the mitochondrial DNA
Wallace, D. C. (1992) · Annual Review of Biochemistry · doi:10.1146/annurev.bi.61.070192.005523 · Cited by 1,319
Crystal structure of a bacteriophage T7 DNA replication complex at 2.2 Å resolution
Doublié, S., Tabor, S., Long, A. M., Richardson, C. C., & Ellenberger, T. (1998) · Nature · doi:10.1038/34593 · Cited by 1,184
Kunkel, T. A., & Bebenek, K. (2000) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.69.1.497 · Cited by 1,003
Self-citationFacile Detection of Mitochondrial DNA Mutations in Tumors and Bodily Fluids
Fliss, M., Usadel, H., Caballero, O. L., Wu, L. J., Buta, M. R., Eleff, S. M., Jen, J., & Sidransky, D. (2000) · Science · doi:10.1126/science.287.5460.2017 · Cited by 821
Michikawa, Y., Mazzucchelli, F., Bresolin, N., Scarlato, G., & Attardi, G. M. (1999) · Science · doi:10.1126/science.286.5440.774 · Cited by 724
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Mutations de l’ADN mitochondrial et cancer colorectal
Lièvre, A., & Laurent‐Puig, P. (2005) · Gastroentérologie Clinique et Biologique · doi:10.1016/s0399-8320(05)80691-8 · Cited by 4
“En effet, cette enzyme, bien qu’étant hautement fidèle, avec moins d’un nucléotide incorporé par erreur sur 250 000 nucléotides synthétisés [38], est responsable d’erreurs de réplication conduisant à des insertions/délétions avec décalage du cadre de lecture au niveau de séquences répétées de l’ADNmt de plus de quatre…”
Structural insight on processivity, human disease and antiviral drug toxicity
Yin, Y. W. (2010) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2010.12.001 · Cited by 4
Somai, S., Aloh, C. H., King, D. E., & Copeland, W. C. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms262110275 · Cited by 3
“The PolG2 accessory subunit, which enhances pol γ processivity, paradoxically reduces both frameshift and base substitution fidelity by facilitating extension of mismatched primer termini [69].”
InfluentialSelf-citationPol γ possesses separate metal binding sites for polymerase and strand displacement functions
Baruch‐Torres, N., Park, J., Mora-Garduño, J. D., Roy, A., Singh, A., Cisneros, G. A., Brieba, L. G., Patel, S. S., & Yin, Y. W. (2026) · Nucleic Acids Research · doi:10.1093/nar/gkag720 · Cited by 3
Singh, L., & Singh, M. K. (2021) · IntechOpen eBooks · doi:10.5772/intechopen.96368 · Cited by 3
“Pol-γ replicates high fidelity mtDNA with one misinsertion in every 500,000 new base pairs due to nucleotide selectivity and proofreading capacity [41].”
BackgroundMitochondrial Genomics and Targeted Toxicities
Copeland, W. C., & Wallace, K. B. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-801238-3.64219-8 · Cited by 3
Self-citationNucleosides, Nucleotides and Nucleic Acids
Wierzchowski, J., & Bzowska, A. (2007) · Cited by 3
Role of Mitochondrial DNA in Inflammatory Airway Diseases
Snyder, R. J., & Kleeberger, S. R. (2021) · Comprehensive physiology · doi:10.1002/cphy.c200010 · Cited by 5
Role of Mitochondrial DNA in Inflammatory Airway Diseases
Snyder, R. J., & Kleeberger, S. R. (2021) · Comprehensive physiology · doi:10.1002/j.2040-4603.2021.tb00159.x · Cited by 2
“Additionally, Pol γ has been found to have a single base substitution error rate of 4.5 × 10 − 5 in the absence of proofreading exonu-cleases (decreasing to 1.0 × 10 − 5 with proofreading) (95).”
InfluentialAccumulated mtDNA mutations are linked to specific impairments in NADH-linked respiration
Franczak, E., Montgomery, M. M., Terwilliger, Z. S., Aruleba, R. T., Krassovskaia, P. M., Boykov, I. N., Hagen, J. T., Pacheco, E. A., Chrest, B. R., Zeczycki, T. N., et al. (2026) · iScience · doi:10.1016/j.isci.2026.115184 · Cited by 2
Lifespan Predicts Mitochondrial Substitution Rates across Vertebrates, but Methodology Matters
Sterling, J. E., Zwonitzer, K., & Havird, J. C. (2026) · Genome Biology and Evolution · doi:10.1093/gbe/evag067 · Cited by 2
“These mutation types were selected based on both previous literature and our own findings, as they represent the most frequent mitochondrial DNA substitutions (Duncan and Miller 1980; Nordmann et al. 1988; Spelbrink et al. 2000; Longley et al. 2001; Song et al. 2005; Zheng et al. 2006).”
Chemical Versus Enzymatic Nucleic Acid Modifications and Genomic Stability
Cortez, J., & Migaud, M. E. (2025) · DNA · doi:10.3390/dna5020019 · Cited by 2
“This occurs be-DNA cause the exonuclease activity of mitochondrial DNA polymerase (pol γ ) fails to recognize 8-oxodGTP as an error, resulting in faulty DNA replication [30].”
Mitochondrial DNA-related disorders: emphasis on mechanisms and heterogeneity
Cagin, U., & Enrı́quez, J. A. (2015) · TURKISH JOURNAL OF BIOLOGY · doi:10.3906/biy-1505-20 · Cited by 2
“Pol γ is one of the most widely studied nuclear genes involved in mtDNA disorders because of its high error rate of 1:50,000 bp (Longley et al., 2001).”
BackgroundHuman mitochondrial DNA repair
Sia, E. A., & Stein, A. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-819656-4.00008-5 · Cited by 2
Paroxysmal kinesigenic dyskinesia associated with a novel POLG variant
Zhou, Y., Zhang, J., Wang, X., Peng, Q., & Shang, X. (2021) · Medicine · doi:10.1097/md.0000000000024395 · Cited by 2
Mitochondrial DNA homeostasis: A novel therapeutic target for neurodegenerative diseases
Fu, T., Chen, X., Zhang, S., Fu, Y., Huang, L., & Xiong, W. (2025) · Neural Regeneration Research · doi:10.4103/nrr.nrr-d-25-00495 · Cited by 1
“It contains a 3′ to 5′ exonuclease domain with exonuclease activity, which ensures efficient proofreading during DNA synthesis, with an error frequency of less than 1 × 10 6 per base (Longley et al., 2001).”
Zhou, F., Jiang, C., Zhang, T., Niu, F., Hu, J., Xu, Y., & Zhang, M. (2025) · Brain and Behavior · doi:10.1002/brb3.71045 · Cited by 1
Li, Z., Dunn, R., Caloren, L. C., Ziada, A. S., Chapman, H. L., Gadawska, I., & Côté, H. C. F. (2026) · Mitochondrion · doi:10.1016/j.mito.2026.102134 · Cited by 1
Mitochondrial Mutagenesis in Aging and Disease
Vermulst, M., Khrapko, K., & Wanagat, J. (2012) · InTech eBooks · doi:10.5772/51099 · Cited by 1
“If this activity is disabled with a point mutation, the spontaneous error spectrum of the enzyme can be exposed[65].”
BackgroundMitochondrial DNA Replication in Health and Disease
Apostolova, N., & Juan, V. (2011) · InTech eBooks · doi:10.5772/19162 · Cited by 1
“It is particularly efficient in base incorporation in short repetitive sequences in which a missinsertion has been estimated to occur only once in every 500000 nucleotides (Longley et al., 2001).”
BackgroundDevadoss, B., Lee, I., & Berdis, A. J. (2012) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2012.08.019 · Cited by 1
Malyarchuk, B. А. (2013) · Molecular Biology · doi:10.1134/s0026893313060083 · Cited by 1
Garcı́a-Villada, L., & Drake, J. W. (2010) · DNA repair · doi:10.1016/j.dnarep.2010.05.002 · Cited by 1
Mitochondrial DNA in neurons and its modulation by neurotoxins
Santos, M. S. (2006) · D-Scholarship@Pitt (University of Pittsburgh) · Cited by 1
Forensic Aspects of mtDNA Analysis
Holland, M. M., & Lauc, G. (2014) · CRC Press eBooks · doi:10.1201/b16512-9 · Cited by 1
Mitochondrial genetics and bipolar disorder
Konradi, C. L., & Kato, T. (2022) · Oxford University Press eBooks · doi:10.1093/med/9780197574522.003.0014 · Cited by 1
Forensic Aspects of mtDNA Analysis
Holland, M. M., & Lauc, G. (2014) · CRC Press eBooks · doi:10.1201/b16512-5 · Cited by 1
The hidden costs of imperfection: transcription errors in protein aggregation diseases
Sun, Y., & Vermulst, M. (2025) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2025.102350 · Cited by 1
Mitochondrial DNA Repair in Mammals
Bogenhagen, D. F. (2006) · Encyclopedia of Life Sciences · doi:10.1038/npg.els.0005969 · Cited by 1
Single-nucleoid imaging in whole cells defines the dynamics of the mtDNA life cyclePreprint
Wolf, D. M., Mjeku, E., Segawa, M., Casey, A. M., Belaadi, N., Franklin, R., Murphy, M. P., Prudent, J., Jones, N. S., & Chinnery, P. F. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.06.01.725017 · Cited by 1
Mutations of mitochondrial DNA polymerase gamma: an important cause of neurological disorders
Luoma, P. T. (2007) · Työväentutkimus Vuosikirja
Nucleoside analog toxicity and nucleoside kinase deficiency : Effects on mitochondrial DNA
Bjerke, M. (2008) · Figshare
Disorders of mitochondrial DNA polymerase: a clinical, biochemical and structural study
Palin, E. (2013) · Työväentutkimus Vuosikirja
Crisis in Energy Metabolism - Mitochondrial Defects and a New Disease Entity
Kollberg, G. (2006) · Gothenburg University Publications Electronic Archive (Gothenburg University)
Mitochondrial dysfunction in ageing and degenerative disease
Wredenberg, A. (2007) · Figshare
Menezes, M. P. (2015) · The Sydney eScholarship Repository (The University of Sydney)
Malyarchuk, B. А. (2004) · Molecular Biology · doi:10.1023/b:mbil.0000032207.61155.ba
“One of the most common errors results from introduction of dGMP to match T and potentially leads to transition T C [ 16 ].”
BackgroundMitochondrial DNA mutations. Brain developmental and ageing consequences, and possible treatments
Ross, J. M. (2012) · Figshare
DNA POLYMERASE ,T HE MITOCHONDRIAL REPLICASE 1
Kaguni, L. S. (2004)
Kollberg, G. (2007)
How mitochondrial DNA mutations affect the growth of MCF-7 clones
Sin, Y. Y. (2006) · UC Research Repository (University of Canterbury) · doi:10.26021/8331
Kinase, N. (2008)
Radzak, S. M. A. (2020) · Universiti Sains Malaysia Institutional Repository (Universiti Sains Malaysia)
Regulation of Human Mitochondrial DNA Replication and Transcription
Mehmedović, M. (2021) · Gothenburg University Publications Electronic Archive (Gothenburg University) · doi:10.13140/rg.2.2.10575.61605
Molecular insights into primer removal during mtDNA replication
Al-Behadili, A. (2021) · Gothenburg University Publications Electronic Archive (Gothenburg University)
John, J. C. S., & John, B. S. (2013) · Springer eBooks · doi:10.1007/978-1-4614-8459-2_5
Anti-Aging Medicine LiteratureWatch
(2002) · Rejuvenation Research · doi:10.1089/109454502317629363
DNA Recognition/Processing | Eukaryotic DNA Polymerase γ
Copeland, W. C. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-809633-8.21269-7
Self-citation(2004) · Encyclopedic Dictionary of Genetics, Genomics and Proteomics · doi:10.1002/0471684228.egp09014
Corey, M. J. (2008) · Wiley eBooks · doi:10.1002/9780470422465.biblio
The effects of HIV and the antiretrovirals on the mitochondria
Barroso, S. E., & Garrabou, G. (2022) · Elsevier eBooks · doi:10.1016/b978-0-323-88462-4.00031-6
Causes and Consequences of Perturbations of the Mitochondrial Genome
King, D. E., Copeland, W. C., Wallace, K. B., & Meyer, J. N. (2024) · Elsevier eBooks · doi:10.1016/b978-0-323-95488-4.00128-5
Self-citationYoshihara, R., Shimakura, Y., Kitamura, S., Satoh, K., Sato, M., Aono, T., Akiyama, Y., Hatakeyama, S., & Tanaka, S. (2024) · Genetics · doi:10.1093/genetics/iyae201
Li, Z., Dunn, R., Caloren, L. C., Ziada, A. S., Chapman, H., Gadawska, I., & Côté, H. C. F. (2025) · bioRxiv · doi:10.1101/2025.06.05.657263
Utveckling och utvärdering av ett fidelitetssystem för DNA polymeraser
Bjurheden, E. (2011)
Bagge, E. K., Fujimori-Tonou, N., Kubota‐Sakashita, M., Kasahara, T., & Kato, T. (2020) · Figshare · doi:10.6084/m9.figshare.13142504
Bagge, E. K., Fujimori-Tonou, N., Kubota‐Sakashita, M., Kasahara, T., & Kato, T. (2020) · Figshare · doi:10.6084/m9.figshare.13142501
Gakely, G. (2026) · Annals of Rejuvenation Science · doi:10.65649/rm9epe20
Peng, X., & Liu, Q. (2026) · Ecotoxicology · doi:10.1007/s10646-026-03081-0
“Pol-γ is a DNA polymerase with high fidelity (Longley et al. 2001 ).”
POLG-related disorders: Clinical and molecular Spectrum in the Saudi population
Mutairi, F. A., Joueidi, F., Mutairi, Z. A. A., Alshalan, M., Eyaid, W., Mushiba, A. M., Alghamdi, M., Tabarki, B. M., Alghamdi, A., Altassan, R., et al. (2026) · Molecular Genetics and Metabolism Reports · doi:10.1016/j.ymgmr.2026.101322
“[4].”
Wu, S., Lujan, S. A., Burkholder, A., Nissanka, N., Longley, M. J., Mieczkowski, P. A., Kunkel, T. A., Moraes, C. T., & Copeland, W. C. (2026) · Nucleic Acids Research · doi:10.1093/nar/gkag648
Self-citationVelioğlu, H., Çiçek, Y., Çelik, M. C., & Bayraktar, A. (2026) · Research Square · doi:10.21203/rs.3.rs-10308549/v1
Castillo-Lizardo, M., & Viguera, E. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27156600
“Repeated sequences thus provide a stable misaligned intermediate that promotes continued polymerisation rather than exonucleolytic correction, explaining why frameshift errors frequently escape exonucleolytic correction [24,25].”
Sokolova, V., Buchel, G., Strock, S., Nayak, A. R., & Temiakov, D. (2026) · Nucleic Acids Research · doi:10.1093/nar/gkag925
“B has been shown to decrease the holoenzyme’s fidelity [ 41 ] and contribute to replisome function [ 42 ], however, these studies did not examine replication initiation and, more Left: RNA primer extension; right: DNA primer extension.”
Molina-Jiménez, M., Baruch‐Torres, N., Díaz‐Quezada, C., & Brieba, L. G. (2026) · PLANT PHYSIOLOGY · doi:10.1093/plphys/kiag721
The effects of HIV and the antiretrovirals on the mitochondria
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Mitochondrial DNA replication and genome stability: From mechanisms to therapeutic strategies
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DNA Polymerase Gamma Mutations in Male Infertility and Ageing
Rovio, A. T. (2006) · Tampere University Institutional Repository (Tampere University)
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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