ArticleHuman molecular genetics2010
mip1 containing mutations associated with mitochondrial disease causes mutagenesis and depletion of mtDNA in Saccharomyces cerevisiae.
Article in Human molecular genetics, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers, 1 of them a synthesis that pooled it.
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Who cites it
31 citing papers in PubMed, 1 synthesis or guideline pooled it, 49 citations in OpenAlex.
- Model systems informing mechanisms and drug discovery: a review ofWellcome open research · 2023Pooled it
- Editing stem cell genomes at scale to measure variant effects in diverse cell and genetic contexts.medRxiv : the preprint server for health sciences · 2025Article
- A steric gate prevents mutagenic dATP incorporation opposite 8-oxo-deoxyguanosine in mitochondrial DNA polymerases.The FEBS journal · 2025Article
- Nuclear Hsp104 safeguards the dormant translation machinery during quiescence.Nature communications · 2024Article
- Regulation with cell size ensures mitochondrial DNA homeostasis during cell growth.Nature structural & molecular biology · 2023Article
- Review
- The Power of Yeast in Modelling Human Nuclear Mutations Associated with Mitochondrial Diseases.Genes · 2021Review
- Human mitochondrial DNA replication machinery and disease.Current opinion in genetics & development · 2016Review
- Mitochondrial DNA maintenance: an appraisal.Molecular and cellular biochemistry · 2015Review
- Yeast model analysis of novel polymerase gamma variants found in patients with autosomal recessive mitochondrial disease.Human genetics · 2015Article
- Genes and Pathways Involved in Adult Onset Disorders Featuring Muscle Mitochondrial DNA Instability.International journal of molecular sciences · 2015Review
- DNA polymerase γ and disease: what we have learned from yeast.Frontiers in genetics · 2015Review
- Alpers disease mutations in human DNA polymerase gamma cause catalytic defects in mitochondrial DNA replication by distinct mechanisms.Frontiers in genetics · 2015Article
- Polymorphisms in DNA polymerase γ affect the mtDNA stability and the NRTI-induced mitochondrial toxicity in Saccharomyces cerevisiae.Mitochondrion · 2015Article
- MMS exposure promotes increased MtDNA mutagenesis in the presence of replication-defective disease-associated DNA polymerase γ variants.PLoS genetics · 2014Article
- Defects of mitochondrial DNA replication.Journal of child neurology · 2014Review
- Mitochondrial genome maintenance in health and disease.DNA repair · 2014Review
- Mapping 136 pathogenic mutations into functional modules in human DNA polymerase γ establishes predictive genotype-phenotype correlations for the complete spectrum of POLG syndromes.Biochimica et biophysica acta · 2014Article
- Yeast cells expressing the human mitochondrial DNA polymerase reveal correlations between polymerase fidelity and human disease progression.The Journal of biological chemistry · 2014Article
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
DNA polymerase gamma (pol gamma) is responsible for replication and repair of mitochondrial DNA (mtDNA). Over 150 mutations in POLG (which encodes pol gamma) have been discovered in patients with mitochondrial disorders including Alpers, progressive external ophthalmoplegia and ataxia-neuropathy syndrome. However, the severity and dominance of many POLG disease-associated mutations are unclear, because they have been reported in sporadic cases. To understand the consequences of pol gamma disease-associated mutations in vivo, we identified dominant and recessive changes in mtDNA mutagenesis, depletion and mitochondrial dysfunction caused by 31 mutations in the conserved regions of the gene, MIP1, which encodes the Saccharomyces cerevisiae ortholog of human pol gamma. Twenty mip1 mutant enzymes were shown to disrupt mtDNA replication and may be sufficient to cause disease. Previously uncharacterized sporadic mutations, Q308H, R807C, G1076V, R1096H and S1104C, caused decreased polymerase activity leading to mtDNA depletion and mitochondrial dysfunction. We present evidence showing a limited role of point mutagenesis by these POLG mutations in mitochondrial dysfunction and disease progression. Instead, most mitochondrial defective mip1 mutants displayed reduced or depleted mtDNA. We also determined that the severity of the phenotype of the mip1 mutant strain correlates with the age of onset of disease associated with the human ortholog. Finally, we demonstrated that increasing nucleotide pools by overexpression of ribonucleotide reductase (RNR1) suppressed mtDNA replication defects caused by several dominant mip1 mutations, and the orthologous human mutations revealed severe nucleotide binding defects.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.