Origins of human mitochondrial point mutations as DNA polymerase γ-mediated errors
Abstract
Mitochondrial mutational spectra in human cells, tissues and derived tumors for bp 10,030-10,130 are essentially identical, suggesting a predominant mutagenic role for endogenous processes. We hypothesized that errors mediated by mitochondrial DNA polymerase gamma were the primary sources of mutations. Point mutations created in this sequence by human DNA pol gamma in vitro were thus compared to the eighteen mutational hotspots, all single base substitutions, previously found in human tissues. The set of concordant hotspots accounted for 83% of these in vivo mutational events. About half of these mutations are insensitive to prolonged heating of DNA during PCR and half increase proportionally with heating time at 98 degrees C. Primary misincorporation errors and miscopying errors past thermal denaturing products such as deaminated cytosines (uracils) thus appear to be of approximately equal importance. For the sequence studied, these data support the conclusion that, endogenous error mediated by DNA pol gamma constitutes the primary source of mitochondrial point mutations in human tissues.
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G:C to T:A transversions are only a small fraction of the mutations found in aged Drosophila or humans.
“Conversely, G:C to T:A transversions are only a small fraction of the mutations found in aged Drosophila (Itsara et al., 2014) or humans (Kennedy et al., 2013; Zheng et al., 2006).”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Zheng et al., 2006
Comparison of mutation spectrum in mtDNA derived from in vivo sources with DNA copied in vitro by the highly purified human Pol γ reveals that over 85% of mutation detected in vivo could be recapitulated in vitro by Pol γ.
“Comparison of mutation spectrum in mtDNA derived from in vivo sources with DNA copied in vitro by the highly purified human Pol γ reveals that over 85% of mutation detected in vivo could be recapitulated in vitro by Pol γ (Zheng et al., 2006).”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Zheng et al., 2006
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- Authors
- Zheng, W., Khrapko, K., Coller, H. A., Thilly, W. G., & Copeland, W. C.
- Affiliations
- Massachusetts Institute of Technology (US)
- Beth Israel Deaconess Medical Center (US)
- Fred Hutch Cancer Center (US)
- National Institute of Environmental Health Sciences (US)
- Corresponding author
- Copeland, William C.
- Venue
- Mutation research. Fundamental and molecular mechanisms of mutagenesis
- Publisher
- Elsevier BV
- Published
- 2006-07
- Volume
- 599
- Issue
- 1-2
- Pages
- 11-20
- ISSN
- 0027-5107 (ISSN-L)
- 1386-1964
- OpenAlex
- W2026609135
- Cited by
- 141
- References
- 51
- Citations by year
- 2026: 2 · 2025: 11 · 2024: 9 · 2023: 11 · 2022: 8 · 2021: 12 · 2020: 17 · 2019: 7 · 2018: 4 · 2017: 10 · 2016: 9 · 2015: 7 · 2014: 9 · 2013: 3 · 2012: 2
- FWCI
- 1.91
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Mutation research. Fundamental and molecular mechanisms of mutagenesis (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Environmental Health Sciences (5P30ES02109, P01-ES07168)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Carcinogens and Genotoxicity Assessment
- Keywords
- mitochondrial DNA, point mutations, DNA polymerase gamma, mutational hotspots, mutational spectra, endogenous mutagenesis, human tissue
- MeSH terms
- DNA Polymerase gamma, Base Sequence, DNA-Directed DNA Polymerase, DNA, Mitochondrial, Humans, Lung, Mutagenesis, Point Mutation, Electrophoresis, Capillary, In Vitro Techniques
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