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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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Citations
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BackgroundThe Base Substitution Fidelity of DNA Polymerase β-dependent Single Nucleotide Base Excision Repair
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BackgroundMutagenesis by Transient Misalignment in the Human Mitochondrial DNA Control Region
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Using the Electroretinogram to Understand How Intraocular Pressure Elevation Affects the Rat Retina
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“POLG is composed of two subunits, a large catalytic α-subunit (Gray and Wong 1992; Graves et al. 1998) that also has exonuclease activity (Longley et al. 2001), and a smaller accessory subunit (POLGB) that appears to be involved in primer recognition and confers improved polymerase capabilities in…”
BackgroundThymidine Phosphorylase Deficiency Causes MNGIE: An Autosomal Recessive Mitochondrial Disorder
Hirano, M., Martí, R., Spinazzola, A., Nishino, I., & Nishigaki, Y. (2004) · Nucleosides Nucleotides & Nucleic Acids · doi:10.1081/ncn-200027485 · Cited by 28
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Hudson, G., Deschauer, M., Taylor, R. W., Hanna, M. G., Fialho, D., Schaefer, A. M., He, L., Blakely, E. L., Turnbull, D. M., & Chinnery, P. F. (2006) · Neurology · doi:10.1212/01.wnl.0000210486.32196.24 · Cited by 28
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“Replication of the mtDNA via POLγ is very precise, since POLγ is a polymerase with proofreading activity that has a low inherent error rate of less than 10−6 [88].”
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Vasileiou, P. V. S., Mourouzis, I. S., & Pantos, C. I. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18081821 · Cited by 27
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BackgroundMitochondrial DNA integrity is not dependent on DNA polymerase-β activity
Hansen, A. B., Griner, N. B., Anderson, J. P., Kujoth, G. C., Prolla, T. A., Loeb, L. A., & Glick, E. (2005) · DNA repair · doi:10.1016/j.dnarep.2005.07.009 · Cited by 27
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ResultSmall molecules restore mutant mitochondrial DNA polymerase activity
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“The human catalytic subunit of Pol g has high base substitution fidelity and the intrinsic 3¢/5¢ exonuclease activity (Longley et al., 2001).”
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Lodi, T., Dallabona, C., Nolli, C., Goffrini, P., Donnini, C., & Baruffini, E. (2015) · Frontiers in Genetics · doi:10.3389/fgene.2015.00106 · Cited by 27
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“The exonuclease activity of Pol-g is important to the fidelity of replication of mtDNA ( 14 – 16 ).”
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Structural basis for DNA proofreading
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“10 errors/10,000 bp [62].”
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“POLcA belongs to the family A polymerases, with an N-terminal 30–50 exonuclease domain, a central linker domain and a C-terminal polymerase domain (2).”
BackgroundMitochondrial DNA common deletion in the human eye: A relation with corneal aging
Gendron, S. P., Mallet, J. D., Bastien, N., & Rochette, P. J. (2012) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2012.01.002 · Cited by 19
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“Longley et al. (2001) have suggested that the homopolymorphic nucleotide tracts in mtDNA were error prone because of the low frameshift fidelity of the DNA polymerase γ that carries out themtDNA replication.”
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Mitochondrial mutations in Caenorhabditis elegans show signatures of oxidative damage and an AT-bias
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“Interestingly, Pol , like other polymerases, is tolerant to a certain level of primer-template mismatch, as long as the 3’ end is complementary (Bebenek and Kunkel, 2000; Longley et al., 2001).”
BackgroundMutation Spectra of Herpes Simplex Virus Type 1 Thymidine Kinase Mutants
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“Not only are many enzymes involved, but they cover DNA replication by gamma polymerase (Longley et al. 2001), postreplicative repair, and asynchronous times of replication between the two strands.”
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“Binding pol gB2 has been shown to increase affinity for primer–template and nucleotides, as well as to decrease fidelity of the catalytic subunit (Johnson et al, 2000; Longley et al, 2001), probably due to the relative displacement of polymerase and exonuclease domains.”
BackgroundCRISPR/Cas9-mediated base editors and their prospects for mitochondrial genome engineering
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Novel POLG mutation in a patient with sensory ataxia, neuropathy, ophthalmoparesis and stroke.
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“coli Pol I,(15) Taq DNA polymerase,(17) and human DNA polymerase γ.(18) The presence of the exonuclease domain imparts at least a 6-fold increase in fidelity, thus showing that it is able to correct most misincorporation events that the polymerase active site makes.”
BackgroundOtten, A. B. C., Stassen, A. P. M., Adriaens, M. E., Gerards, M., Dohmen, R. G. J., Timmer, A. J., Vanherle, S. J. V., Kamps, R., Boesten, I., Vanoevelen, J. M., et al. (2016) · Genetics · doi:10.1534/genetics.116.194035 · Cited by 15
“The absence of de novo indels is in line with a study in human germlinemtDNA (Rebolledo-Jaramillo et al. 2014) and suggests that the error rate of POLG for insertions and deletions is lower than for substitutions, which has been reported previously (Longley et al. 2001).”
BackgroundResultFidelity and Processivity of Reverse Transcription by the Human Mitochondrial DNA Polymerase
Lee, H. R., & Johnson, K. A. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m705392200 · Cited by 14
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“Besides, DNA polymerase c had been shown to cause frame-shift errors in homopolymeric runs, suggesting that these regions are potential hot spots in mtDNA.(43) Achanta et al.”
BackgroundLow Variability of the POLG (CAG) n Repeat in North Eurasian Populations
Malyarchuk, B. А., Papuga, M., Grzybowski, T., Rogozin, I. B., Woźniak, M., Derenko, M. V., Rychkov, S., Czarny, J., Zakharov, I. A., & Miścicka‐Śliwka, D. (2005) · Human Biology · doi:10.1353/hub.2005.0050 · Cited by 12
“Among these genes, mtDNA polymerase gamma (POLG; MIM 174763) has been identified as an enzyme directly involved in induction of mtDNA mutations (Longley et al. 2001; Van Goethem et al. 2001; Ponamarev et al. 2002; Del Bo et al. 2003).”
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Iterated function systems for DNA replication
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“with nucleic DNA, mtDNA is more susceptible to genetic alterations, as mitochondria harbor inefficient DNA repair systems [3,4].”
BackgroundVadakedath, S., Kandi, V., Jayashankar, C. A., Vijayan, S., Achyut, K. C., Uppuluri, S., Reddy, P. K. K., Ramesh, M., & Kumar, P. (2023) · Cureus · doi:10.7759/cureus.39812 · Cited by 15
“Moreover, the fidelity of DNA polymerase gamma (PLOG) that carries out the mtDNA replication process is lower than that found in the nucleus and is not severely affected [41-46].”
BackgroundJandová, J., Eshaghian, A., Shi, M., Li, M., King, L. E., Janda, J., & Sligh, J. E. (2011) · Journal of Investigative Dermatology · doi:10.1038/jid.2011.320 · Cited by 10
“The occurrence of an insertion mutation within a homopolymeric tract may highlight a potential weakness in the ability of mitochondrial DNA polymerase γ to repair UVA induced damage within the mtDNA (Longley et al., 2001).”
BackgroundMitochondrial DNA maintenance in Drosophila melanogaster
Rodrigues, A. P., Novaes, A. C., Ciesielski, G. L., & Oliveira, M. T. (2022) · Bioscience Reports · doi:10.1042/bsr20211693 · Cited by 9
Coordinated DNA polymerization by Polγ and the region of LonP1 regulated proteolysis
Riccio, A. A., Brannon, A. J., Krahn, J. M., Bouvette, J., Williams, J. G., Borgnia, M. J., & Copeland, W. C. (2024) · Nucleic Acids Research · doi:10.1093/nar/gkae539 · Cited by 9
Self-citationKinetic Analysis of the Unique Error Signature of Human DNA Polymerase ν
Arana, M. E., Potapova, O., Kunkel, T. A., & Joyce, C. M. (2011) · Biochemistry · doi:10.1021/bi201197p · Cited by 9
Self-citationHuman DNA Polymerase ν Catalyzes Correct and Incorrect DNA Synthesis with High Catalytic Efficiency
Gowda, A. S. P., Moldovan, G., & Spratt, T. E. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.653287 · Cited by 9
High frequency of somatic mutations in rat liver mitochondrial DNA
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MtDNA maintenance and stability genes: MNGIE and mtDNA depletion syndromes
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“28 Exo domain contains three highly conserved motifs, called exo1 , exo2 and exo3 .”
BackgroundRefolding active human DNA polymerase ν from inclusion bodies
Arana, M. E., Powell, G. K., Edwards, L. L., Kunkel, T. A., & Petrovich, R. M. (2009) · Protein Expression and Purification · doi:10.1016/j.pep.2009.10.010 · Cited by 8
Self-citationMitochondrial DNA mutations and aging
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Peralta-Castro, A., García‐Medel, P. L., Baruch‐Torres, N., Trasviña‐Arenas, C. H., Juárez-Quintero, V., Morales‐Vázquez, C. M., & Brieba, L. G. (2020) · Genes · doi:10.3390/genes11111370 · Cited by 8
Complete nucleotide sequence of the A+T-rich region of Drosophila mauritiana mitochondrial DNA
Sugihara, K., Yui, R., Ibaragi, Y., & Matsuura, E. T. (2006) · Genes & Genetic Systems · doi:10.1266/ggs.81.21 · Cited by 8
Impact of mitochondria on nuclear genome stability
Karthikeyan, G., & Resnick, M. A. (2004) · DNA repair · doi:10.1016/j.dnarep.2004.07.004 · Cited by 8
Pharmacogenomics, Toxicogenomics, and DNA Polymerase γ
Lewis, W. (2007) · The Journal of Infectious Diseases · doi:10.1086/513879 · Cited by 9
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Pérez-Arnaiz, P., Lázaro, J. M., Salas, M., & de Vega, M. (2009) · Journal of Molecular Biology · doi:10.1016/j.jmb.2009.06.068 · Cited by 7
POLG exon 22 skipping induced by different mechanisms in two unrelated cases of Alpers syndrome
de Camaret, B. M., Chassagne, M., Mayençon, M., Padet, S., Crehalet, H., Clerc-Renaud, P., Rouvet, I., Zabot, M. T., Rivier, F., Sarda, P., et al. (2010) · Mitochondrion · doi:10.1016/j.mito.2010.07.011 · Cited by 7
“The mature protein is a 135-kDa polypeptide composed of three functional domains: an amino-terminal 3′-5′ exonuclease (exo) domain responsible for the fidelity of mtDNA replication (Longley et al., 2001), a linker domain and a carboxy-terminal polymerase (pol) domain (Ropp and Copeland, 1996; Lecrenier et al.”
BackgroundCiesielska, E. J., Kim, S., Bisimwa, H. M., Grier, C., Rahman, M. M., Young, C. K. J., Young, M. J., Oliveira, M. T., & Ciesielski, G. L. (2021) · Mitochondrion · doi:10.1016/j.mito.2021.09.010 · Cited by 6
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mtDNA replication, maintenance, and nucleoid organization
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“Parameters that could be altered by processivity factors include kinetic barriers to extending a mismatch or bypassing a lesion, the ability of the polymerase to partition its activity between the physically distinct exo and pol sites, the relative accessibility of the exo and pol sites, and dissociation of polymerase…”
BackgroundYusoff, A. A. M., Radzak, S. M. A., & Khair, S. Z. N. M. (2022) · Współczesna Onkologia · doi:10.5114/wo.2022.115674 · Cited by 5
“However, mtDNA polγ has low frameshift fidelity and is prone to slippage, thus resulting in lower proofreading efficiency [63].”
BackgroundCommon Principles Underlie Mitochondrial DNA Heteroplasmy Dynamics in the Germline and Soma
Ryall, C., Chinnery, P. F., & van den Ameele, J. (2026) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-120324-032239 · Cited by 5
Exonuclease action of replicative polymerase gamma drives damage-induced mitochondrial DNA clearance
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“In vitro, PolG (without exonuclease activity) displays an error rate of 15 × 10 − 6 per nucleotide (Longley et al, 2001).”
Ciesielski, G. L., Kim, S., Pontes, C. D. B., & Kaguni, L. S. (2021) · Frontiers in Genetics · doi:10.3389/fgene.2021.721864 · Cited by 5
“…high processivity of ~100 nt (Longley et al., 1998b; Johnson et al., 2000), as compared to that of 1–15 nt of other DNA polymerase catalytic subunits (McHenry and Kornberg, 1977; Hori et al., 1979; Lee et al., 2010), and exhibits higher fidelity than Pol γ holoenzyme (Longley et al., 2001).”
BackgroundJohn, J. C. S., & John, B. S. (2011) · Springer eBooks · doi:10.1007/978-1-4419-6857-9_6 · Cited by 5
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Mitochondrial DNA Instability Is Common in HIV-Exposed Uninfected Newborns
Monnin, A., Desquiret‐Dumas, V., Méda, N., Goudenège, D., Bris, C., Kankasa, C., Singata‐Madliki, M., Tylleskär, T., Procaccio, V., Nagot, N., et al. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10112399 · Cited by 4
“Physiologically, mtDNA has a higher rate of point mutations and rearrangements than nuclear DNA, due to the lack of histone scaffolding, a reduced efficacy of mtDNA repair mechanisms and a lower processivity of the DNA polymerase γ as compared to other cellular DNA polymerases [19,20].”
BackgroundConstruction of a highly error-prone DNA polymerase for developing organelle mutation systems
Ji, J., & Day, A. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa929 · Cited by 4
“A 20-fold increase in error rate was reported for the 3 –5 exonuclease-deficient human mitochondrial gamma DNA polymerase (64).”
Mitochondrial Disease: Maintenance of Mitochondrial Genome and Molecular Diagnostics
Kang, D., & Hamasaki, N. (2006) · Advances in clinical chemistry · doi:10.1016/s0065-2423(06)42006-0 · Cited by 4
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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