ArticleProceedings of the National Academy of Sciences of the United States of America2002
High incidence of epithelial cancers in mice deficient for DNA polymerase delta proofreading.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2002. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 95 papers.
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Who cites it
95 citing papers in PubMed, 172 citations in OpenAlex.
- A phase II clinical trial of toripalimab in advanced solid tumors with polymerase epsilon/polymerase delta (POLE/POLD1) mutation.Signal transduction and targeted therapy · 2024Trial
- Immune Checkpoint Blockade Delays Cancer Development and Extends Survival in DNA Polymerase Mutator Syndromes.Cancer 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
- Carcinogenesis trajectories.Frontiers in cell and developmental biology · 2025Article
- Altered dNTP pools accelerate tumor formation in mice.Nucleic acids research · 2024Article
- Human DNA polymerase ε is a source of C>T mutations at CpG dinucleotides.Nature genetics · 2024Article
- Discovery of recessive effect of human polymerase δ proofreading deficiency through mutational analysis of POLD1-mutated normal and cancer cells.European journal of human genetics : EJHG · 2024Article
- Article
- Non-canonical binding of the Chaetomium thermophilum PolD4 N-terminal PIP motif to PCNA involves Q-pocket and compact 2-fork plug interactions but no 3The FEBS journal · 2023Article
- Exonucleases: Degrading DNA to Deal with Genome Damage, Cell Death, Inflammation and Cancer.Cells · 2022Review
- Article
- Increased somatic mutation burdens in normal human cells due to defective DNA polymerases.Nature genetics · 2021Article
- 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
- Limiting DNA polymerase delta alters replication dynamics and leads to a dependence on checkpoint activation and recombination-mediated DNA repair.PLoS genetics · 2021Article
- Cancers from NovelCancer research · 2020Article
- John W. (Jan) Drake: A Biochemical View of a GeneticistGenetics · 2020Article
- DNA Polymerases at the Eukaryotic Replication Fork Thirty Years after: Connection to Cancer.Cancers · 2020Review
- POLE and POLD1 pathogenic variants in the proofreading domain in papillary thyroid cancer.Endocrine connections · 2020Article
- The identification of six risk genes for ovarian cancer platinum response based on global network algorithm and verification analysis.Journal of cellular and molecular medicine · 2020Article
- POLE Mutation Spectra Are Shaped by the Mutant Allele Identity, Its Abundance, and Mismatch Repair Status.Molecular cell · 2020Article
35 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
Mutations are a hallmark of cancer. Normal cells minimize spontaneous mutations through the combined actions of polymerase base selectivity, 3' --> 5' exonucleolytic proofreading, mismatch correction, and DNA damage repair. To determine the consequences of defective proofreading in mammals, we created mice with a point mutation (D400A) in the proofreading domain of DNA polymerase delta (poldelta, encoded by the Pold1 gene). We show that this mutation inactivates the 3' --> 5' exonuclease of poldelta and causes a mutator and cancer phenotype in a recessive manner. By 18 months of age, 94% of homozygous Pold1(D400A/D400A) mice developed cancer and died (median survival = 10 months). In contrast, only 3-4% of Pold1(+/D400A) and Pold1(+/+) mice developed cancer in this time frame. Of the 66 tumors arising in 49 Pold1(D400A/D400A) mice, 40 were epithelial in origin (carcinomas), 24 were mesenchymal (lymphomas and sarcomas), and two were composite (teratomas); one-third of these animals developed tumors in more than one tissue. Skin squamous cell carcinoma was the most common tumor type, occurring in 60% of all Pold1(D400A/D400A) mice and in 90% of those surviving beyond 8 months of age. These data show that poldelta proofreading suppresses spontaneous tumor development and strongly suggest that unrepaired DNA polymerase errors contribute to carcinogenesis. Mice deficient in poldelta proofreading provide a tractable model to study mechanisms of epithelial tumorigenesis initiated by a mutator phenotype.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.