ArticleGenetics2013
Emergence of DNA polymerase ε antimutators that escape error-induced extinction in yeast.
Article in Genetics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 47 citations in OpenAlex.
- PolED: a manually curated database of functional studies of POLE and POLD1 variants reported in humans.Database : the journal of biological databases and curation · 2025Article
- The divergence of mutation rates and spectra across the Tree of Life.EMBO reports · 2023Review
- Enhanced polymerase activity permits efficient synthesis by cancer-associated DNA polymerase ϵ variants at low dNTP levels.Nucleic acids research · 2022Article
- Article
- Review
- Strand discrimination in DNA mismatch repair.DNA repair · 2021Review
- Checkpoint-mediated DNA polymerase ε exonuclease activity curbing counteracts resection-driven fork collapse.Molecular cell · 2021Article
- Mutagenic mechanisms of cancer-associated DNA polymerase ϵ alleles.Nucleic acids research · 2021Article
- DNA Polymerases at the Eukaryotic Replication Fork Thirty Years after: Connection to Cancer.Cancers · 2020Review
- Mismatch repair and DNA polymerase δ proofreading prevent catastrophic accumulation of leading strand errors in cells expressing a cancer-associated DNA polymerase ϵ variant.Nucleic acids research · 2020Article
- Article
- POLE Mutation Spectra Are Shaped by the Mutant Allele Identity, Its Abundance, and Mismatch Repair Status.Molecular cell · 2020Article
- DNA polymerase δ proofreads errors made by DNA polymerase ε.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- POLE proofreading defects: Contributions to mutagenesis and cancer.DNA repair · 2019Review
- A simple but profound mutation in mouse DNA polymerase ε drives tumorigenesis.The Journal of clinical investigation · 2018Article
- Distinct mutational signatures characterize concurrent loss of polymerase proofreading and mismatch repair.Nature communications · 2018Article
- Article
- Alterations in cellular metabolism triggered byProceedings of the National Academy of Sciences of the United States of America · 2017Article
- Normally lethal amino acid substitutions suppress an ultramutator DNA Polymerase δ variant.Scientific reports · 2017Article
- Review
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
DNA polymerases (Pols) ε and δ perform the bulk of yeast leading- and lagging-strand DNA synthesis. Both Pols possess intrinsic proofreading exonucleases that edit errors during polymerization. Rare errors that elude proofreading are extended into duplex DNA and excised by the mismatch repair (MMR) system. Strains that lack Pol proofreading or MMR exhibit a 10- to 100-fold increase in spontaneous mutation rate (mutator phenotype), and inactivation of both Pol δ proofreading (pol3-01) and MMR is lethal due to replication error-induced extinction (EEX). It is unclear whether a similar synthetic lethal relationship exists between defects in Pol ε proofreading (pol2-4) and MMR. Using a plasmid-shuffling strategy in haploid Saccharomyces cerevisiae, we observed synthetic lethality of pol2-4 with alleles that completely abrogate MMR (msh2Δ, mlh1Δ, msh3Δ msh6Δ, or pms1Δ mlh3Δ) but not with partial MMR loss (msh3Δ, msh6Δ, pms1Δ, or mlh3Δ), indicating that high levels of unrepaired Pol ε errors drive extinction. However, variants that escape this error-induced extinction (eex mutants) frequently emerged. Five percent of pol2-4 msh2Δ eex mutants encoded second-site changes in Pol ε that reduced the pol2-4 mutator phenotype between 3- and 23-fold. The remaining eex alleles were extragenic to pol2-4. The locations of antimutator amino-acid changes in Pol ε and their effects on mutation spectra suggest multiple mechanisms of mutator suppression. Our data indicate that unrepaired leading- and lagging-strand polymerase errors drive extinction within a few cell divisions and suggest that there are polymerase-specific pathways of mutator suppression. The prevalence of suppressors extragenic to the Pol ε gene suggests that factors in addition to proofreading and MMR influence leading-strand DNA replication fidelity.
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Registered trials
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