The Fidelity of Human DNA Polymerase γ with and without Exonucleolytic Proofreading and the p55 Accessory Subunit
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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 when copying long homopolymeric sequences.
“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]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredThe intrinsic 3′ → 5′ exonuclease activity of Pol γ improves replication fidelity at least 20-fold.
“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
High fidelity of Pol γ is due to high nucleotide selectivity and exonucleolytic proofreading.
“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
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.
“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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“The exonuclease domain of POLGA is required for exonucleolytic proofreading which, when associated with high nucleotide selectivity, confers high fidelity DNA synthesis [61].”
BackgroundMitochondrial DNA Alterations in Cancer
Copeland, W. C., Wachsman, J. T., Johnson, F. M., & Penta, J. S. (2002) · Cancer Investigation · doi:10.1081/cnv-120002155 · Cited by 230 · see citing works
“Despite the high fidelity of DNA synthesis, DNA polymerase gamma has been shown to cause frame-shift errors in homopolymeric runs suggesting that these regions are potential hot spots in mtDNA (67).”
BackgroundSelf-citationEvolving Views of DNA Replication (In)FidelityPreprint
Kunkel, T. A. (2009) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2009.74.027 · Cited by 206 · see citing works
Self-citationNishigaki, Y., Martí, R., Copeland, W. C., & Hirano, M. (2003) · Journal of Clinical Investigation · doi:10.1172/jci17828 · Cited by 191 · see citing works
“It has been shown that direct misincorporation of a deoxyguanosine monophosphate (dGMP) opposite a template thymine residue (T·dGMP) is a common event (30, 31).”
BackgroundSelf-citationThe Role of Mitochondrial DNA Mutations in Mammalian Aging
Kujoth, G. C., Bradshaw, P. C., Haroon, S., & Prolla, T. A. (2007) · PLoS Genetics · doi:10.1371/journal.pgen.0030024 · Cited by 186 · see citing works
“It has conserved polymerase and exonuclease domains, the combined action of which results in high-fidelity mtDNA replication with human POLG displaying an average error frequency of ;1 error/500,000 bp in vitro [22,23].”
BackgroundDeBalsi, K. L., Hoff, K. E., & Copeland, W. C. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2016.04.006 · Cited by 180 · see citing works
Self-citationMitochondrial DNA damage and its consequences for mitochondrial gene expression
Cline, S. D. (2012) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2012.06.002 · Cited by 203 · see citing works
Functional Human Mitochondrial DNA Polymerase γ Forms a Heterotrimer
Yakubovskaya, E., Chen, Z., Carrodeguas, J. A., Kisker, C., & Bogenhagen, D. F. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m509730200 · Cited by 176 · see citing works
Song, S., Pursell, Z. F., Copeland, W. C., Longley, M. J., Kunkel, T. A., & Mathews, C. K. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0500253102 · Cited by 176 · see citing works
Self-citationMitochondrial DNA replication in mammalian cells: overview of the pathway
Falkenberg, M. (2018) · Essays in Biochemistry · doi:10.1042/ebc20170100 · Cited by 166 · see citing works
Defects in mitochondrial DNA replication and human disease
Copeland, W. C. (2011) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.3109/10409238.2011.632763 · Cited by 163 · see citing works
“This signature mutation suggests a “next-nucleotide effect” caused by the more common T:dGMP misinsertion (Longley et al., 2001) which is quickly extended by the elevated dTTP concentration resulting from TP deficiency in the mitochondria of MNGIE cells (Nishigaki et al., 2003).”
BackgroundSelf-citationPonamarev, M. V., Longley, M. J., Nguyen, D., Kunkel, T. A., & Copeland, W. C. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.c200100200 · Cited by 156 · see citing works
Self-citationLow-fidelity DNA synthesis by human DNA polymerase theta
Arana, M. E., Seki, M., Wood, R. D., Rogozin, I. B., & Kunkel, T. A. (2008) · Nucleic Acids Research · doi:10.1093/nar/gkn310 · Cited by 153 · see citing works
“62% for exonuclease-deficient pol g (22).”
Self-citationMechanism of a genetic glissando*: structural biology of indel mutations
García–Díaz, M., & Kunkel, T. A. (2006) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2006.02.004 · Cited by 149 · see citing works
Self-citationOrigins of human mitochondrial point mutations as DNA polymerase γ-mediated errors
Zheng, W., Khrapko, K., Coller, H. A., Thilly, W. G., & Copeland, W. C. (2006) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/j.mrfmmm.2005.12.012 · Cited by 141 · see citing works
Self-citationConsequences of mutations in human DNA polymerase γ
Longley, M. J., Graziewicz, M. A., Bienstock, R. J., & Copeland, W. C. (2005) · Gene · doi:10.1016/j.gene.2005.03.029 · Cited by 140 · see citing works
Self-citationMitochondrial genome maintenance in health and disease
Copeland, W. C., & Longley, M. J. (2014) · DNA repair · doi:10.1016/j.dnarep.2014.03.010 · Cited by 137 · see citing works
Self-citationGraziewicz, M. A., Longley, M. J., Bienstock, R. J., Zeviani, M., & Copeland, W. C. (2004) · Nature Structural & Molecular Biology · doi:10.1038/nsmb805 · Cited by 131 · see citing works
“We have also produced a 3′→5′ exonuclease-deficient derivative of pol γ and studied the fidelity of DNA replication by pol &gamma”
MethodSelf-citationUnique Error Signature of the Four-subunit Yeast DNA Polymerase ϵ
Shcherbakova, P. V., Pavlov, Y. I., Chilkova, O., Rogozin, I. B., Johansson, E., & Kunkel, T. A. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m306893200 · Cited by 129 · see citing works
Self-citationRoles of DNA Polymerases in Replication, Repair, and Recombination in Eukaryotes
Pavlov, Y. I., Shcherbakova, P. V., & Rogozin, I. B. (2006) · International Review of Cytology · doi:10.1016/s0074-7696(06)55002-8 · Cited by 123 · see citing works
Accumulation of point mutations in mitochondrial DNA of aging mice
Khaidakov, M., Heflich, R. H., Manjanatha, M. G., Myers, M. B., & Aidoo, A. (2003) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/s0027-5107(03)00010-1 · Cited by 123 · see citing works
Lewis, W., Day, B. J., Kohler, J. J., Hosseini, S. H., Chan, S. S. L., Green, E. C., Haase, C. P., Keebaugh, E. S., Long, R., Ludaway, T., et al. (2007) · Laboratory Investigation · doi:10.1038/labinvest.3700523 · Cited by 121 · see citing works
“Exonuclease activity allows for proofreading of the growing DNA strand and increases faithful copying of mtDNA.(4) Other investigators employed transgenic mouse (TG) models of defective mtDNA replication that expressed exonucleolytic proofreading-deficient Pol g and that yielded increased mtDNA mutations(5) and cardio…”
BackgroundSelf-citationLimits and patterns of cytomegalovirus genomic diversity in humans
Renzette, N., Pokalyuk, C., Gibson, L. L., Bhattacharjee, B., Schleiss, M. R., Hamprecht, K., Yamamoto, A. Y., Mussi‐Pinhata, M. M., Britt, W. J., Jensen, J. D., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1501880112 · Cited by 120 · see citing works
“Furthermore, extrinsic or accessory factors can alter polymerase fidelity (74, 75), and the interaction of HSV and HCMV polymerases with their cognate accessory proteins, UL42 and UL44, respectively, has been shown to differ at the molecular level (76) as have the quaternary structures of the accessory proteins (77).”
BackgroundReplication and Transcription of Human Mitochondrial DNA
Falkenberg, M., Larsson, N., & Gustafsson, C. M. (2024) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-052621-092014 · Cited by 123 · see citing works
Multiple Functions of DNA Polymerases
García–Díaz, M., & Bębenek, K. (2007) · Critical Reviews in Plant Sciences · doi:10.1080/07352680701252817 · Cited by 116 · see citing works
“As expected of a replicative polymerase, Pol γ has high fidelity and high processivity (Longley et al., 2001).”
BackgroundMitochondrial DNA replication and disease: insights from DNA polymerase γ mutations
Stumpf, J. D., & Copeland, W. C. (2010) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-010-0530-4 · Cited by 115 · see citing works
“Mutations in the catalytic aspartates disrupt exonuclease activity increasing base substitutions 20-fold in vitro [95] and 500-fold in S.”
BackgroundSelf-citationPre-Steady-State Kinetic Studies of the Fidelity of Sulfolobus solfataricus P2 DNA Polymerase IV
Fiala, K. A., & Suo, Z. (2004) · Biochemistry · doi:10.1021/bi0357457 · Cited by 115 · see citing works
Wu, E. Y., & Beese, L. S. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.191130 · Cited by 113 · see citing works
Wu, Z., Waneka, G., Broz, A. K., King, C. R., & Sloan, D. B. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2001998117 · Cited by 112 · see citing works
Chen, J. Z., Gökden, N., Greene, G. F., Mukunyadzi, P., & Kadlubar, F. F. (2002) · PubMed · Cited by 112 · see citing works
The clinical diagnosis of POLG disease and other mitochondrial DNA depletion disorders
Cohen, B. H., & Naviaux, R. K. (2010) · Methods · doi:10.1016/j.ymeth.2010.05.008 · Cited by 107 · see citing works
Low Fidelity DNA Synthesis by a Y Family DNA Polymerase Due to Misalignment in the Active Site
Kokoska, R. J., Bębenek, K., Boudsocq, F., Woodgate, R., & Kunkel, T. A. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m202021200 · Cited by 107 · see citing works
Self-citationRole of Mitochondria in Cancer Stem Cell Resistance
García-Heredia, J. M., & Carnero, A. (2020) · Cells · doi:10.3390/cells9071693 · Cited by 108 · see citing works
The Frameshift Infidelity of Human DNA Polymerase λ
Bebenek, K., Garcia-Diaz, M., Blanco, L., & Kunkel, T. A. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m305705200 · Cited by 104 · see citing works
Self-citationFidelity of the Human Mitochondrial DNA Polymerase
Lee, H. R., & Johnson, K. A. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m607964200 · Cited by 101 · see citing works
Oxidative damage diminishes mitochondrial DNA polymerase replication fidelity
Anderson, A. P., Luo, X., Russell, W. K., & Yin, Y. W. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz1018 · Cited by 100 · see citing works
“Pol replication error frequency is 2 × 10−6 where the exo proofreading contributes 101–102-fold towards error reduction (28,30,41), similar to other high fidelity polymerases (29,42).”
BackgroundPOLG mutations in sporadic mitochondrial disorders with multiple mtDNA deletions
Fonzo, A. D., Bordoni, A., Crimi, M., Galbiati, S., Bo, R. D., Bresolin, N., & Comi, G. P. (2003) · Human Mutation · doi:10.1002/humu.9203 · Cited by 97 · see citing works
“The b subunit is believed to increase the polymerase processivity (Longley et al., 2001).”
BackgroundChan, S. S. L., Longley, M. J., & Copeland, W. C. (2006) · Human Molecular Genetics · doi:10.1093/hmg/ddl424 · Cited by 96 · see citing works
Self-citationDuan, K., Gu, Q., Petralia, R. S., Wang, Y., Panja, D., Liu, X., Lehmann, M. L., Zhu, H., Zhu, J., & Li, Z. (2021) · Neuron · doi:10.1016/j.neuron.2021.09.008 · Cited by 95 · see citing works
Mutations in the mitochondrial DNA D-loop region are frequent in cervical cancer.
Sharma, H., Singh, A., Sharma, C., Jain, S., & Singh, N. (2005) · Cancer Cell International · doi:10.1186/1475-2867-5-34 · Cited by 95 · see citing works
“In addition, a study [26] suggests that homopolymorphic nucleotide tracts in mtDNA are error prone because of the low frameshift fidelity of the DNA polymerase gamma that carries out the mtDNA replication.”
BackgroundDNA Polymerase Gamma in Mitochondrial DNA Replication and Repair
Copeland, W. C., & Longley, M. J. (2003) · The Scientific World JOURNAL · doi:10.1100/tsw.2003.09 · Cited by 91 · see citing works
“Kinetic analyses indicate that p55 lowers fidelity of replication by promoting extension of mismatched termini[59].”
BackgroundSelf-citationGraziewicz, M. A., Bienstock, R. J., & Copeland, W. C. (2007) · Human Molecular Genetics · doi:10.1093/hmg/ddm227 · Cited by 93 · see citing works
“The observed hydrogenbonding interactions between these residues help to explain the high fidelity of nucleotide incorporation by pol g (29).”
BackgroundSelf-citationKushnir, V. A., & Lewis, W. (2011) · Fertility and Sterility · doi:10.1016/j.fertnstert.2011.05.094 · Cited by 93 · see citing works
Decreased Mitochondrial DNA Mutagenesis in Human Colorectal Cancer
Ericson, N. G., Kulawiec, M., Vermulst, M., Sheahan, K. D., O'Sullivan, J. N., Salk, J. J., & Bielas, J. H. (2012) · PLoS Genetics · doi:10.1371/journal.pgen.1002689 · Cited by 87 · see citing works
“Interestingly, the majority of the clonally expanded mutations observed in carcinomas are C:G to T:A transitions (Table 1), which is similar to that previously reported in human colorectal tumors [16] and to the spectrum of random mutations in normal and adenoma tissue (Figure 3A), but is markedly different from the s…”
ResultTrace amounts of 8-oxo-dGTP in mitochondrial dNTP pools reduce DNA polymerase replication fidelity
Pursell, Z. F., McDonald, J., Mathews, C. K., & Kunkel, T. A. (2008) · Nucleic Acids Research · doi:10.1093/nar/gkn062 · Cited by 87 · see citing works
“DNA polymerase g fidelity was measured as described ( 7 ).”
InfluentialSelf-citationUltrasensitive deletion detection links mitochondrial DNA replication, disease, and aging
Lujan, S. A., Longley, M. J., Humble, M. H., Lavender, C. A., Burkholder, A., Blakely, E. L., Alston, C. L., Gorman, G. S., Turnbull, D. M., McFarland, R., et al. (2020) · Genome biology · doi:10.1186/s13059-020-02138-5 · Cited by 84 · see citing works
Self-citationLim, S. E., Ponamarev, M. V., Longley, M. J., & Copeland, W. C. (2003) · Journal of Molecular Biology · doi:10.1016/s0022-2836(03)00405-4 · Cited by 85 · see citing works
Self-citationThe Mitochondrial DNA Polymerase in Health and Disease
Copeland, W. C. (2009) · Sub-cellular biochemistry/Subcellular biochemistry · doi:10.1007/978-90-481-3471-7_11 · Cited by 85 · see citing works
“Comparing the in vitro rates of base substitution errors for the exonuclease deficient and proficient forms of human pol γ indicated that the proofreading function contributes at least 20-fold to the fidelity of base selection (Longley et al., 2001).”
BackgroundInfluentialSelf-citationMitochondrial DNA maintenance: an appraisal
Akhmedov, A. T., & Marı́n-Garcı́a, J. (2015) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-015-2532-x · Cited by 82 · see citing works
Polg2 is essential for mammalian embryogenesis and is required for mtDNA maintenance
Humble, M. M., Young, M. J., Foley, J. F., Pandiri, A. R., Travlos, G. S., & Copeland, W. C. (2013) · Human Molecular Genetics · doi:10.1093/hmg/dds506 · Cited by 78 · see citing works
Updating the Free Radical Theory of Aging
Ziada, A. S., Smith, M.-S. R., & Côté, H. C. F. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.575645 · Cited by 80 · see citing works
“, 2013), believed to be the hallmark of mitochondrial polymerase γ errors rather than oxidative damage (Spelbrink et al., 2000; Longley et al., 2001; Kauppila et al., 2017).”
BackgroundHow DNA polymerases catalyse replication and repair with contrasting fidelity
Wu, W.-J., Yang, W., & Tsai, M.-D. (2017) · Nature Reviews Chemistry · doi:10.1038/s41570-017-0068 · Cited by 76 · see citing works
RPA and PCNA suppress formation of large deletion errors by yeast DNA polymerase δ
Fortune, J. M., Stith, C. M. W., Kissling, G. E., Burgers, P., & Kunkel, T. A. (2006) · Nucleic Acids Research · doi:10.1093/nar/gkl403 · Cited by 71 · see citing works
“This is interesting in light of studies indicating that proteins that increase processivity promote extension of base–base mismatches by T7 DNA polymerase (18), T4 DNA polymerase (19) and human DNA polymerase g (20).”
BackgroundSelf-citationAlternative solutions and new scenarios for translesion DNA synthesis by human PrimPol
Martínez-Jiménez, M. I., García-Gómez, S., Bębenek, K., Sastre-Moreno, G., Calvo, P. A., Díaz‐Talavera, A., Kunkel, T. A., & Blanco, L. (2015) · DNA repair · doi:10.1016/j.dnarep.2015.02.013 · Cited by 70 · see citing works
Self-citationOrigins of mtDNA mutations in ageing
Szczepanowska, K., & Trifunović, A. (2017) · Essays in Biochemistry · doi:10.1042/ebc20160090 · Cited by 70 · see citing works
Structural basis for processivity and antiviral drug toxicity in human mitochondrial DNA replicase
Szymański, M. R., Kuznetsov, V. B., Shumate, C. K., Meng, Q., Lee, Y., Patel, G., Patel, S. S., & Yin, Y. W. (2015) · The EMBO Journal · doi:10.15252/embj.201591520 · Cited by 67 · see citing works
“The error frequency of Pol c is 10 (cid:2) 5 during DNA replication, comparable to other high-fidelity DNA polymerases (Longley et al , 2001; Lee & Johnson, 2006).”
Malyarchuk, B. А., Rogozin, I. B., Berikov, V., & Derenko, M. V. (2002) · Human Genetics · doi:10.1007/s00439-002-0740-4 · Cited by 68 · see citing works
“The dislocation mutagenesis was also revealed for errors produced by DNA polymerase γ in vitro ( Longley et al. 2001 ).”
BackgroundMethodInfluentialFunctions of Eukaryotic DNA Polymerases
Shcherbakova, P. V., Bębenek, K., & Kunkel, T. A. (2003) · Science of Aging Knowledge Environment · doi:10.1126/sageke.2003.8.re3 · Cited by 69 · see citing works
Self-citationChromosome organization and chromatin modification: influence on genome function and evolution
Holmquist, G. P., & Ashley, T. (2006) · Cytogenetic and Genome Research · doi:10.1159/000093326 · Cited by 67 · see citing works
“Different DNA polymerases do make different sets of base substitution errors when reading undamaged DNA (Osheroff et al., 1999; Kunkel and Bebenek, 2000; Ohashi et al., 2000; Longley et al., 2001; Kunkel et al., 2003).”
BackgroundMammalian mitochondrial DNA replication and mechanisms of deletion formation
Falkenberg, M., & Gustafsson, C. M. (2020) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409238.2020.1818684 · Cited by 65 · see citing works
Separating and Segregating the Human Mitochondrial Genome
Nicholls, T. J. J., & Gustafsson, C. M. (2018) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2018.08.007 · Cited by 62 · see citing works
High frequency of mitochondrial genome instability in human endometrial carcinomas
Liu, V. W. S., Yang, H., Wang, Y., Tsang, P. C. K., Cheung, A., Chiu, P. M., Ng, T. Y., Wong, L. C., NAGLEY, P., & Ngan, H. (2003) · British Journal of Cancer · doi:10.1038/sj.bjc.6601110 · Cited by 61 · see citing works
“In addition, a recent study (Longley et al, 2001) suggests that the homopolymorphic nucleotide tracts in mtDNA are error-prone because of the low frameshift fidelity of the DNA polymerase gamma that carries out the mtDNA replication.”
BackgroundThe Complicated Nature of Somatic mtDNA Mutations in Aging
Sánchez-Contreras, M., & Kennedy, S. R. (2022) · Frontiers in Aging · doi:10.3389/fragi.2021.805126 · Cited by 61 · see citing works
“In vitro assays involving the copying of DNA by Pol-γ show predominantly G → A/C → T mutations, even when controlling for potential confounders such as heat-induced template deamination (Longley et al., 2001; Zheng et al., 2006).”
BackgroundDepletion of the other genome-mitochondrial DNA depletion syndromes in humans
Elpeleg, O. N., Mandel, H., & Saada, A. (2002) · Journal of Molecular Medicine · doi:10.1007/s00109-002-0343-5 · Cited by 59 · see citing works
“However, low frameshift fidelity is evident when homopolymeric sequences longer than four nucleotides are copied [ 21 ].”
BackgroundDefects of Mitochondrial DNA Replication
Copeland, W. C. (2014) · Journal of Child Neurology · doi:10.1177/0883073814537380 · Cited by 54 · see citing works
“Comparing the in vitro error rates for the exonuclease proficient and deficient forms of pol g indicates that exonucleolytic proofreading contributes at least 20-fold to the fidelity of mitochondrial DNA synthesis.(50) The exonuclease function is also necessary to suppress mitochondrial DNA deletions between direct re…”
BackgroundSelf-citationMitochondrial DNA repair: a novel therapeutic target for heart failure
Marı́n-Garcı́a, J. (2016) · Heart Failure Reviews · doi:10.1007/s10741-016-9543-x · Cited by 54 · see citing works
“, cleaving nucleic acid by removal of single nucleotides from the end of the chain) proofreading activity and high nucleotide selectivity of POLc are responsible for the high fidelity of mtDNA replication (by proofreading and errorchecking DNA) [17].”
BackgroundNuclear Transfer: Preservation of a Nuclear Genome at the Expense of Its Associated mtDNA Genome(s)
Bowles, E. J., Campbell, K., & John, J. C. S. (2007) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/s0070-2153(06)77010-7 · Cited by 54 · see citing works
Davidson, J. F. (2003) · Nucleic Acids Research · doi:10.1093/nar/gkg667 · Cited by 54 · see citing works
“This ®nding is contrary to what was observed for both T7 DNA polymerase and Pol g in the absence of their respective processivity cofactors (17,18).”
ResultGraziewicz, M. A. (2004) · Nucleic Acids Research · doi:10.1093/nar/gkh213 · Cited by 52 · see citing works
“With all four nucleotides present, pol g with the accessory subunit inserted one or more nucleotides past the end of the template, most likely through a template dislocation intermediate or strand slippage mechanism that we previously documented for pol g (37).”
BackgroundSanchez-Contreras, M., Sweetwyne, M. T., Kohrn, B. F., Tsantilas, K. A., Hipp, M. J., Schmidt, E. K., Fredrickson, J., Whitson, J. A., Campbell, M., Rabinovitch, P., et al. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab901 · Cited by 42 · see citing works
Kasiviswanathan, R., Longley, M. J., Chan, S. S. L., & Copeland, W. C. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.011940 · Cited by 52 · see citing works
Self-citationDecoding Warburg's hypothesis: tumor-related mutations in the mitochondrial respiratory chain
García-Heredia, J. M., & Carnero, A. (2015) · Oncotarget · doi:10.18632/oncotarget.6057 · Cited by 51 · see citing works
“In addition, mtDNA replication by DNA polymerase γ occurs with lower fidelity than with nuclear DNA, due to mtDNA’s inferior proof-reading function [35].”
BackgroundMutations in DNA polymerase gamma cause error prone DNA synthesis in human mitochondrial disorders.
Copeland, W. C., Ponamarev, M. V., Nguyen, D., Kunkel, T. A., & Longley, M. J. (2003) · Acta Biochimica Polonica · doi:10.18388/abp.2003_3723 · Cited by 51 · see citing works
“The human catalytic subunit of pol has high base substitution fidelity that results from high nucleotide selectivity and exonucleolytic proofreading (Johnson & Johnson, 2001; Longley et al., 2001).”
BackgroundSelf-citationThymidine phosphorylase mutations cause instability of mitochondrial DNA
Hirano, M., Lagier‐Tourenne, C., Valentino, M. L., Martí, R., & Nishigaki, Y. (2005) · Gene · doi:10.1016/j.gene.2005.04.041 · Cited by 51 · see citing works
Stumpf, J. D., Bailey, C. M., Spell, D., Stillwagon, M., Anderson, K. S., & Copeland, W. C. (2010) · Human Molecular Genetics · doi:10.1093/hmg/ddq089 · Cited by 48 · see citing works
Self-citationPlant organellar DNA polymerases are replicative and translesion DNA synthesis polymerases
Baruch‐Torres, N., & Brieba, L. G. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx744 · Cited by 48 · see citing works
Linking DNA polymerase theta structure and function in health and disease
Beagan, K., & McVey, M. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-2078-9 · Cited by 47 · see citing works
“This is reflected in its fairly low misincorporation rate of 2 9 10 for single base pair substitutions [13].”
The interface of transcription and DNA replication in the mitochondria
Kasiviswanathan, R., Collins, T., & Copeland, W. C. (2011) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2011.12.005 · Cited by 46 · see citing works
“Use of the human exonuclease-proficient pol γ [37] demonstrated that pol γ has high DNA synthesis fidelity due to high nucleotide selectivity and efficient proofreading [45].”
BackgroundSelf-citationA unique error signature for human DNA polymerase ν
Arana, M. E., Takata, K., García–Díaz, M., Wood, R. D., & Kunkel, T. A. (2006) · DNA repair · doi:10.1016/j.dnarep.2006.09.012 · Cited by 46 · see citing works
“3′ exonuclease that can proofread mistakes [5].”
Self-citationMitochondrial DNA sequence variants in epithelial ovarian tumor subtypes and stages.
Aikhionbare, F. O., Mehrabi, S., Kumaresan, K., Zavareh, M., Olatinwo, M. O., Odunsi, K. O., & Partridge, E. E. (2007) · Journal of Carcinogenesis · doi:10.1186/1477-3163-6-1 · Cited by 46 · see citing works
“Different mechanisms have been put forward to explain the genomic instability of this stretch of cytosine residues [34-37].”
BackgroundChen, J. Z. (2003) · Carcinogenesis · doi:10.1093/carcin/bgg102 · Cited by 46 · see citing works
“It is less probable that a by-pass polymerase plays a role in mitochondrial mutagenesis in human tumors because the human mtDNA polymerase g (pol g) is so far the only polymerase identified in mitochondria and is involved in both mtDNA replication and repair ( 28 ).”
BackgroundMitochondrial DNA mosaicism in normal human somatic cells
An, J., Nam, C. H., Kim, R., Lee, Y., Won, H., Park, S., Lee, W. H., Park, H., Yoon, S.-S., An, Y., et al. (2024) · Nature Genetics · doi:10.1038/s41588-024-01838-z · Cited by 46 · see citing works
“Interestingly, our estimate was within the range of error rates of polymerase γ ( POLG ), the mitochondrial genome’s DNA polymerase 56,57 .”
Kong, Y. X. G., Bergen, N. V., Trounce, I. A., Bui, B. V., Chrysostomou, V., Waugh, H. S., Vingrys, A. J., & Crowston, J. G. (2011) · Aging Cell · doi:10.1111/j.1474-9726.2011.00690.x · Cited by 43 · see citing works
“The exonuclease activity proofreads nascent mtDNA and ensures faithful replication of the mitochondrial genome (Longley et al., 2001).”
BackgroundThe role of DNA exonucleases in protecting genome stability and their impact on ageing
Mason, P. A., & Cox, L. S. (2011) · AGE · doi:10.1007/s11357-011-9306-5 · Cited by 43 · see citing works
“Table 1 Exonucleases discussed in this article Exonuclease Polarity Metabolic pathway References Polymerase δ, ε, γ 3′-5′ Replication (proofreading) Hubscher et al. 2002; Tran et al. 1999; Longley et al. 2001 ExoN 3′-5′ Unknown—proofreading?”
BackgroundPathogenicity in POLG syndromes: DNA polymerase gamma pathogenicity prediction server and database
Nurminen, A., Farnum, G. A., & Kaguni, L. S. (2017) · BBA Clinical · doi:10.1016/j.bbacli.2017.04.001 · Cited by 45 · see citing works
Unexpected Role for Helicobacter pylori DNA Polymerase I As a Source of Genetic Variability
García‐Ortiz, M. V., Marsin, S., Arana, M. E., Gasparutto, D., Guérois, R., Kunkel, T. A., & Radicella, J. P. (2011) · PLoS Genetics · doi:10.1371/journal.pgen.1002152 · Cited by 43 · see citing works
“62% for exonuclease-deficient pol c [25].”
Self-citationZiada, A. S., Lu, M. Y., Ignas‐Menzies, J., Paintsil, E., Li, M., Ogbuagu, O. E., Saberi, S., Hsieh, A. Y. Y., Sattha, B., Harrigan, P. R., et al. (2019) · Aging Cell · doi:10.1111/acel.13018 · Cited by 40 · see citing works
- 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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