ArticleNature communications2019
Structural consequence of the most frequently recurring cancer-associated substitution in DNA polymerase ε.
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 38 papers.
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Who cites it
38 citing papers in PubMed.
- Deficiency in POLE Exonuclease Causes Synthetic Lethality in Highly Aneuploid Cancer Cells.Cancer research · 2026Article
- ctDNA guided management of POLE mutant GI malignancies promotes exceptional responses and prolonged survival to immunotherapy.Frontiers in immunology · 2026Article
- Comprehensive Analysis of Human Colorectal Cancers Harboring Polymerase Epsilon Mutations.International journal of molecular sciences · 2025Article
- 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
- Functions, interactions and prognostic role ofJournal of gynecologic oncology · 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
- Computational studies on the functional and structural impact of pathogenic mutations in enzymes.Protein science : a publication of the Protein Society · 2025Review
- DNA polymerase zeta can efficiently replicate structures formed by AT/TA repeat sequences and prevent their deletion.Nucleic acids research · 2025Article
- Clamping Pol ε to the leading strand.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
- 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
- A simple bypass assay for DNA polymerases shows that cancer-associated hypermutating variants exhibit differences in vitro.The FEBS journal · 2023Article
- A sensor complements the steric gate when DNA polymerase ϵ discriminates ribonucleotides.Nucleic acids research · 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
- Extrinsic proofreading.DNA repair · 2022Review
- Enhanced polymerase activity permits efficient synthesis by cancer-associated DNA polymerase ϵ variants at low dNTP levels.Nucleic acids research · 2022Article
Corrections and comments
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Authors and funding
6 authors.
Funding
Abstract
The most frequently recurring cancer-associated DNA polymerase ε (Pol ε) mutation is a P286R substitution in the exonuclease domain. While originally proposed to increase genome instability by disrupting exonucleolytic proofreading, the P286R variant was later found to be significantly more pathogenic than Pol ε proofreading deficiency per se. The mechanisms underlying its stronger impact remained unclear. Here we report the crystal structure of the yeast orthologue, Pol ε-P301R, complexed with DNA and an incoming dNTP. Structural changes in the protein are confined to the exonuclease domain, with R301 pointing towards the exonuclease site. Molecular dynamics simulations suggest that R301 interferes with DNA binding to the exonuclease site, an outcome not observed with the exonuclease-inactive Pol ε-D290A,E292A variant lacking the catalytic residues. These results reveal a distinct mechanism of exonuclease inactivation by the P301R substitution and a likely basis for its dramatically higher mutagenic and tumorigenic effects.
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