ArticleNature communications2019
A recurrent cancer-associated substitution in DNA polymerase ε produces a hyperactive enzyme.
Article in Nature communications, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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Who cites it
52 citing papers in PubMed.
- Interpreting the effects of DNA polymerase variants at the structural level.Molecular oncology · 2026Article
- The Role of Mesothelin in Gynecological Tumors and Its Significance in Targeted Therapies-A Review.Cancers · 2026Review
- Light and Enzymatic Cooperative Response in Supramolecular Fibers: A Synergistic Strategy for Potential Drug Delivery Applications.Biomacromolecules · 2026Article
- The human primosome requires replication protein A when copying DNA with inverted repeats.Nucleic acids research · 2025Article
- POLE Mutation Associated With Microsatellite Instability and High Tumor Mutational Burden Confers Exquisite Sensitivity to Immune Checkpoint Inhibitor Therapy in Non-Small Cell Lung Cancer: A Case Report and Genomic Database Analysis.Clinical lung cancer · 2025Article
- A conserved thumb domain insertion in DNA polymerase epsilon supports processive DNA synthesis.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
- Cancer, metastasis, and the epigenome.Molecular cancer · 2024Review
- Article
- Molecular Classification of Endometrial Cancer and Its Impact on Therapy Selection.International journal of molecular sciences · 2024Review
- Melanoma-Derived DNA Polymerase Theta Variants Exhibit Altered DNA Polymerase Activity.Biochemistry · 2024Article
- Exploring Co-occurring POLE Exonuclease and Non-exonuclease Domain Mutations and Their Impact on Tumor Mutagenicity.Cancer research communications · 2024Article
- DNA polymerase ε and δ variants drive mutagenesis in polypurine tracts in human tumors.Cell reports · 2024Article
- The P286R mutation of DNA polymerase ε activates cancer-cell-intrinsic immunity and suppresses endometrial tumorigenesis via the cGAS-STING pathway.Cell death & disease · 2024Article
- Exploring the basis of heterogeneity of cancer aggressiveness among the mutated POLE variants.Life science alliance · 2024Review
- Embracing Heterogeneity: Challenging the Paradigm of Replisomes as Deterministic Machines.Chemical reviews · 2023Review
- A simple bypass assay for DNA polymerases shows that cancer-associated hypermutating variants exhibit differences in vitro.The FEBS journal · 2023Article
- Article
- Balancing act of a leading strand DNA polymerase-specific domain and its exonuclease domain promotes genome-wide sister replication fork symmetry.Genes & development · 2023Article
- The mismatch recognition protein MutSα promotes nascent strand degradation at stalled replication forks.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
Corrections and comments
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Authors and funding
7 authors.
Funding
Abstract
Alterations in the exonuclease domain of DNA polymerase ε (Polε) cause ultramutated tumors. Severe mutator effects of the most common variant, Polε-P286R, modeled in yeast suggested that its pathogenicity involves yet unknown mechanisms beyond simple proofreading deficiency. We show that, despite producing a catastrophic amount of replication errors in vivo, the yeast Polε-P286R analog retains partial exonuclease activity and is more accurate than exonuclease-dead Polε. The major consequence of the arginine substitution is a dramatically increased DNA polymerase activity. This is manifested as a superior ability to copy synthetic and natural templates, extend mismatched primer termini, and bypass secondary DNA structures. We discuss a model wherein the cancer-associated substitution limits access of the 3'-terminus to the exonuclease site and promotes binding at the polymerase site, thus stimulating polymerization. We propose that the ultramutator effect results from increased polymerase activity amplifying the contribution of Polε errors to the genomic mutation rate.
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