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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
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“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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“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
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 65
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
“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
Sanchez-Contreras, M., & Kennedy, S. R. (2022) · Frontiers in Aging · doi:10.3389/fragi.2021.805126 · Cited by 60
“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
“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
“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
Marín-García, J. (2016) · Heart Failure Reviews · doi:10.1007/s10741-016-9543-x · Cited by 55
“, 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
Davidson, J. F. (2003) · Nucleic Acids Research · doi:10.1093/nar/gkg667 · Cited by 54
“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
“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).”
BackgroundSánchez-Contreras, M., Sweetwyne, M. T., Kohrn, B. F., Tsantilas, K. A., Hipp, M. J., Schmidt, E. K., Fredrickson, J., Whitson, J. A., Campbell, M. D., Rabinovitch, P. S., et al. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab901 · Cited by 54
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 55
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 53
“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
“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
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 47
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
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
“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 45
“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
“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
“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
“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 50
“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
“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 46
“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
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
“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
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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