ArticleThe Journal of biological chemistry2014
Yeast cells expressing the human mitochondrial DNA polymerase reveal correlations between polymerase fidelity and human disease progression.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 21 citations in OpenAlex.
- Antifungal and Therapeutic Evaluation of l- and d‑Enantiomers of a Plant Defensin-Inspired Peptide againstACS omega · 2026Article
- Progressive cognitive impairment and ventricular tachycardia in a boy with biallelic POLG variants and a de novo RYR2 variation.Scientific reports · 2026Article
- The Saccharomyces Genome Database-a history of ideas and accomplishments, 1994-2026.FEMS yeast research · 2026Article
- Alzheimer's Disease: Significant Benefit from the Yeast-Based Models.International journal of molecular sciences · 2023Review
- mtDNA Maintenance and Alterations in the Pathogenesis of Neurodegenerative Diseases.Current neuropharmacology · 2023Review
- Review
- The Power of Yeast in Modelling Human Nuclear Mutations Associated with Mitochondrial Diseases.Genes · 2021Review
- A Yeast-Based Model for Hereditary Motor and Sensory Neuropathies: A Simple System for Complex, Heterogeneous Diseases.International journal of molecular sciences · 2020Review
- RNA Aptamers Rescue Mitochondrial Dysfunction in a Yeast Model of Huntington's Disease.Molecular therapy. Nucleic acids · 2018Article
- DNA Polymerase Beta Participates in Mitochondrial DNA Repair.Molecular and cellular biology · 2017Article
- A multi-systemic mitochondrial disorder due to a dominant p.Y955H disease variant in DNA polymerase gamma.Human molecular genetics · 2017Article
- Efforts to make and apply humanized yeast.Briefings in functional genomics · 2016Review
- Scope and limitations of yeast as a model organism for studying human tissue-specific pathways.BMC systems biology · 2015Article
- Yeast model analysis of novel polymerase gamma variants found in patients with autosomal recessive mitochondrial disease.Human genetics · 2015Article
- Polymorphisms in DNA polymerase γ affect the mtDNA stability and the NRTI-induced mitochondrial toxicity in Saccharomyces cerevisiae.Mitochondrion · 2015Article
- Alpers disease mutations in human DNA polymerase gamma cause catalytic defects in mitochondrial DNA replication by distinct mechanisms.Frontiers in genetics · 2015Article
- DNA polymerase γ and disease: what we have learned from yeast.Frontiers in genetics · 2015Review
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
Abstract
Mutations in the human mitochondrial polymerase (polymerase-γ (Pol-γ)) are associated with various mitochondrial disorders, including mitochondrial DNA (mtDNA) depletion syndrome, Alpers syndrome, and progressive external opthamalplegia. To correlate biochemically quantifiable defects resulting from point mutations in Pol-γ with their physiological consequences, we created "humanized" yeast, replacing the yeast mtDNA polymerase (MIP1) with human Pol-γ. Despite differences in the replication and repair mechanism, we show that the human polymerase efficiently complements the yeast mip1 knockouts, suggesting common fundamental mechanisms of replication and conserved interactions between the human polymerase and other components of the replisome. We also examined the effects of four disease-related point mutations (S305R, H932Y, Y951N, and Y955C) and an exonuclease-deficient mutant (D198A/E200A). In haploid cells, each mutant results in rapid mtDNA depletion, increased mutation frequency, and mitochondrial dysfunction. Mutation frequencies measured in vivo equal those measured with purified enzyme in vitro. In heterozygous diploid cells, wild-type Pol-γ suppresses mutation-associated growth defects, but continuous growth eventually leads to aerobic respiration defects, reduced mtDNA content, and depolarized mitochondrial membranes. The severity of the Pol-γ mutant phenotype in heterozygous diploid humanized yeast correlates with the approximate age of disease onset and the severity of symptoms observed in humans.
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