ArticleNucleic acids research2020
Mismatch repair and DNA polymerase δ proofreading prevent catastrophic accumulation of leading strand errors in cells expressing a cancer-associated DNA polymerase ϵ variant.
Article in Nucleic acids research, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 18 citations in OpenAlex.
- Article
- The proofreading mechanism of the human leading-strand DNA polymerase ε holoenzyme.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Article
- S-phase checkpoint prevents leading strand degradation from strand-associated nicks at stalled replication forks.Nucleic acids research · 2024Article
- Exploring the basis of heterogeneity of cancer aggressiveness among the mutated POLE variants.Life science alliance · 2024Review
- Polymorphism ofInternational journal of molecular sciences · 2023Article
- Enhanced polymerase activity permits efficient synthesis by cancer-associated DNA polymerase ϵ variants at low dNTP levels.Nucleic acids research · 2022Article
- Review
- Expression of the cancer-associated DNA polymerase ε P286R in fission yeast leads to translesion synthesis polymerase dependent hypermutation and defective DNA replication.PLoS genetics · 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
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Substitutions in the exonuclease domain of DNA polymerase ϵ cause ultramutated human tumors. Yeast and mouse mimics of the most common variant, P286R, produce mutator effects far exceeding the effect of Polϵ exonuclease deficiency. Yeast Polϵ-P301R has increased DNA polymerase activity, which could underlie its high mutagenicity. We aimed to understand the impact of this increased activity on the strand-specific role of Polϵ in DNA replication and the action of extrinsic correction systems that remove Polϵ errors. Using mutagenesis reporters spanning a well-defined replicon, we show that both exonuclease-deficient Polϵ (Polϵ-exo-) and Polϵ-P301R generate mutations in a strictly strand-specific manner, yet Polϵ-P301R is at least ten times more mutagenic than Polϵ-exo- at each location analyzed. Thus, the cancer variant remains a dedicated leading-strand polymerase with markedly low accuracy. We further show that P301R substitution is lethal in strains lacking Polδ proofreading or mismatch repair (MMR). Heterozygosity for pol2-P301R is compatible with either defect but causes strong synergistic increases in the mutation rate, indicating that Polϵ-P301R errors are corrected by Polδ proofreading and MMR. These data reveal the unexpected ease with which polymerase exchange occurs in vivo, allowing Polδ exonuclease to prevent catastrophic accumulation of Polϵ-P301R-generated errors on the leading strand.
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