ArticleHuman molecular genetics2007
The DNA polymerase gamma Y955C disease variant associated with PEO and parkinsonism mediates the incorporation and translesion synthesis opposite 7,8-dihydro-8-oxo-2'-deoxyguanosine.
Article in Human molecular genetics, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.
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Who cites it
53 citing papers in PubMed, 92 citations in OpenAlex.
- Mitochondrial DNA: a molecular switch driving sterile neuroinflammation.Translational neurodegeneration · 2026Review
- Brain somatic mutations in Alzheimer's disease: linking genetic mosaicism to neurodegeneration.Molecular neurodegeneration · 2025Review
- A steric gate prevents mutagenic dATP incorporation opposite 8-oxo-deoxyguanosine in mitochondrial DNA polymerases.The FEBS journal · 2025Article
- Modelling POLG mutations in mice unravels a critical role of POLγΒ in regulating phenotypic severity.Nature communications · 2025Article
- Evolution and maintenance of mtDNA gene content across eukaryotes.The Biochemical journal · 2024Review
- Structural and Molecular Basis for Mitochondrial DNA Replication and Transcription in Health and Antiviral Drug Toxicity.Molecules (Basel, Switzerland) · 2023Review
- Premature aging is associated with higher levels of 8-oxoguanine and increased DNA damage in the Polg mutator mouse.Aging cell · 2022Article
- The Complicated Nature of Somatic mtDNA Mutations in Aging.Frontiers in aging · 2022Article
- Dynamic features of human mitochondrial DNA maintenance and transcription.Frontiers in cell and developmental biology · 2022Review
- Polymerase γ efficiently replicates through many natural template barriers but stalls at the HSP1 quadruplex.The Journal of biological chemistry · 2020Article
- Unbiased PCR-free spatio-temporal mapping of the mtDNA mutation spectrum reveals brain region-specific responses to replication instability.BMC biology · 2020Article
- Mitochondrial pathways in human health and aging.Mitochondrion · 2020Review
- Mitonuclear Interactions in the Maintenance of Mitochondrial Integrity.Life (Basel, Switzerland) · 2020Review
- Senescent Cell Depletion Through Targeting BCL-Family Proteins and Mitochondria.Frontiers in physiology · 2020Review
- Base-excision repair deficiency alone or combined with increased oxidative stress does not increase mtDNA point mutations in mice.Nucleic acids research · 2018Article
- Review
- Inherited mitochondrial genomic instability and chemical exposures.Toxicology · 2017Review
- DNA Polymerase Beta Participates in Mitochondrial DNA Repair.Molecular and cellular biology · 2017Article
- Clinical Reasoning: A 58-year-old man with progressive ptosis and walking difficulty.Neurology · 2017Article
- A multi-systemic mitochondrial disorder due to a dominant p.Y955H disease variant in DNA polymerase gamma.Human molecular genetics · 2017Article
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Authors and funding
3 authors at 3 institutions in 2 countries.
Funding
Abstract
Mitochondrial DNA is replicated and repaired by DNA polymerase gamma (pol gamma), encoded by the POLG gene. The Y955C substitution in POLG leads to autosomal dominant progressive external ophthalmoplegia (PEO) with other severe phenotypes. PEO patients with this mutation can further develop parkinsonism or premature ovarian failure. Mouse and yeast models with this mutation show enhanced amounts of oxidative lesions and increased mtDNA damage. In DNA pol gamma, Tyr955 plays a critical role in catalysis and high fidelity DNA synthesis. 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxo-dG) is one of the most common oxidative lesions in DNA and can promote transversion mutations. Mitochondria are thought to be a major source of endogenous reactive oxygen species that can react with dG to form 8-oxo-dG as one of the more common products. DNA polymerases can mitigate mutagenesis by 8-oxo-dG through allosteric interactions from amino acid side chains, which limit the anti-conformation of the 8-oxo-dG template base during translesion DNA synthesis. Here, we show that the Y955C pol gamma displays relaxed discrimination when either incorporating 8-oxo-dGTP or translesion synthesis opposite 8-oxo-dG. Molecular modeling and biochemical analysis suggest that this residue, Tyr955, in conjunction with Phe961 helps attenuate the anti-conformation in human pol gamma for error free bypass of 8-oxo-dG and substitution to Cys allows the mutagenic syn conformation. Collectively, these results offer a biochemical link between the observed oxidative stress in model systems and parkinsonism in patients, suggesting that patients harboring the Y955C POLG mutation may undergo enhanced oxidative stress and DNA mutagenesis.
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