ArticleNucleic acids research2022
Probing the mechanisms of two exonuclease domain mutators of DNA polymerase ϵ.
Article in Nucleic acids research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 12 citations in OpenAlex.
- Interpreting the effects of DNA polymerase variants at the structural level.Molecular oncology · 2026Article
- Replicative DNA polymerase epsilon and delta holoenzymes show wide-ranging inhibition at G-quadruplexes in the human genome.Nucleic acids research · 2025Article
- DNA polymerase zeta can efficiently replicate structures formed by AT/TA repeat sequences and prevent their deletion.Nucleic acids research · 2025Article
- 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
- Structural basis for processive daughter-strand synthesis and proofreading by the human leading-strand DNA polymerase Pol ε.Nature structural & molecular biology · 2024Article
- Exploring Co-occurring POLE Exonuclease and Non-exonuclease Domain Mutations and Their Impact on Tumor Mutagenicity.Cancer research communications · 2024Article
- Exploring the basis of heterogeneity of cancer aggressiveness among the mutated POLE variants.Life science alliance · 2024Review
- Article
- Characterization of POLE c.1373A > T p.(Tyr458Phe), causing high cancer risk.Molecular genetics and genomics : MGG · 2023Article
- Extrinsic proofreading.DNA repair · 2022Review
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
We report the properties of two mutations in the exonuclease domain of the Saccharomyces cerevisiae DNA polymerase ϵ. One, pol2-Y473F, increases the mutation rate by about 20-fold, similar to the catalytically dead pol2-D290A/E290A mutant. The other, pol2-N378K, is a stronger mutator. Both retain the ability to excise a nucleotide from double-stranded DNA, but with impaired activity. pol2-Y473F degrades DNA poorly, while pol2-N378K degrades single-stranded DNA at an elevated rate relative to double-stranded DNA. These data suggest that pol2-Y473F reduces the capacity of the enzyme to perform catalysis in the exonuclease active site, while pol2-N378K impairs partitioning to the exonuclease active site. Relative to wild-type Pol ϵ, both variants decrease the dNTP concentration required to elicit a switch between proofreading and polymerization by more than an order of magnitude. While neither mutation appears to alter the sequence specificity of polymerization, the N378K mutation stimulates polymerase activity, increasing the probability of incorporation and extension of a mismatch. Considered together, these data indicate that impairing the primer strand transfer pathway required for proofreading increases the probability of common mutations by Pol ϵ, elucidating the association of homologous mutations in human DNA polymerase ϵ with cancer.
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