ArticleNucleic acids research2021
Mutagenic mechanisms of cancer-associated DNA polymerase ϵ alleles.
Article in Nucleic acids research, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 25 citations in OpenAlex.
- Interpreting the effects of DNA polymerase variants at the structural level.Molecular oncology · 2026Article
- A redefined InDel taxonomy provides insights into mutational signatures.Nature genetics · 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
- The theory of massively repeated evolution and full identifications of cancer-driving nucleotides (CDNs).eLife · 2024Article
- DNA polymerase ε and δ variants drive mutagenesis in polypurine tracts in human tumors.Cell reports · 2024Article
- A simple bypass assay for DNA polymerases shows that cancer-associated hypermutating variants exhibit differences in vitro.The FEBS journal · 2023Article
- Genome instability footprint under rapamycin and hydroxyurea treatments.PLoS genetics · 2023Article
- Enhanced polymerase activity permits efficient synthesis by cancer-associated DNA polymerase ϵ variants at low dNTP levels.Nucleic acids research · 2022Article
- Efficient discrimination against RNA-containing primers by human DNA polymerase ε.Scientific reports · 2022Article
- Review
- Mouse model and human patient data reveal critical roles for Pten and p53 in suppressing POLE mutant tumor development.NAR cancer · 2022Article
- 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
- DNA Polymerases at the Eukaryotic Replication Fork Thirty Years after: Connection to Cancer.Cancers · 2020Review
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
A single amino acid residue change in the exonuclease domain of human DNA polymerase ϵ, P286R, is associated with the development of colorectal cancers, and has been shown to impart a mutator phenotype. The corresponding Pol ϵ allele in the yeast Saccharomyces cerevisiae (pol2-P301R), was found to drive greater mutagenesis than an entirely exonuclease-deficient Pol ϵ (pol2-4), an unexpected phenotype of ultra-mutagenesis. By studying the impact on mutation frequency, type, replication-strand bias, and sequence context, we show that ultra-mutagenesis is commonly observed in yeast cells carrying a range of cancer-associated Pol ϵ exonuclease domain alleles. Similarities between mutations generated by these alleles and those generated in pol2-4 cells indicate a shared mechanism of mutagenesis that yields a mutation pattern similar to cancer Signature 14. Comparison of POL2 ultra-mutator with pol2-M644G, a mutant in the polymerase domain decreasing Pol ϵ fidelity, revealed unexpected analogies in the sequence context and strand bias of mutations. Analysis of mutational patterns unique to exonuclease domain mutant cells suggests that backtracking of the polymerase, when the mismatched primer end cannot be accommodated in the proofreading domain, results in the observed insertions and T>A mutations in specific sequence contexts.
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