ArticleProceedings of the National Academy of Sciences of the United States of America2010
A cancer-associated DNA polymerase delta variant modeled in yeast causes a catastrophic increase in genomic instability.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 papers.
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Who cites it
56 citing papers in PubMed, 72 citations in OpenAlex.
- Combined immunodeficiency caused by a loss-of-function mutation in DNA polymerase delta 1.The Journal of allergy and clinical immunology · 2020Trial
- A dominant mutation in tomato DNA POLYMERASE DELTA 1 causes geminivirus DNA replication catastrophe.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Archaeal family B DNA polymerase facilitates lagging strand DNA replication in the Thermococcales.Nucleic acids research · 2026Article
- Allelic differences within DNA polymerase delta subunit 1 correlate with geminivirus resistance in diverse plants.G3 (Bethesda, Md.) · 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
- 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
- Exploring the Role of Clustered Mutations in Carcinogenesis and Their Potential Clinical Implications in Cancer.International journal of molecular sciences · 2024Review
- DNA polymerase ε and δ variants drive mutagenesis in polypurine tracts in human tumors.Cell reports · 2024Article
- Exploring the basis of heterogeneity of cancer aggressiveness among the mutated POLE variants.Life science alliance · 2024Review
- Signification and Application of Mutator and Antimutator Phenotype-Induced Genetic Variations in Evolutionary Adaptation and Cancer Therapeutics.Journal of microbiology (Seoul, Korea) · 2023Review
- Case Report: Cancer spectrum and genetic characteristics of aFrontiers in oncology · 2023Article
- Unraveling the impact of a germline heterozygousFrontiers in molecular biosciences · 2023Article
- Enhanced polymerase activity permits efficient synthesis by cancer-associated DNA polymerase ϵ variants at low dNTP levels.Nucleic acids research · 2022Article
- Mutations in DNA polymerase δ subunit 1 co-segregate with CMD2-type resistance to Cassava Mosaic Geminiviruses.Nature communications · 2022Article
- Review
- Probing altered enzyme activity in the biochemical characterization of cancer.Bioscience reports · 2022Review
- Scrutinizing Deleterious Nonsynonymous SNPs and Their Effect on Human POLD1 Gene.Genetics research · 2022Article
- Compensation for the absence of the catalytically active half of DNA polymerase ε in yeast by positively selected mutations in CDC28.Genetics · 2021Article
- MIF is a 3' flap nuclease that facilitates DNA replication and promotes tumor growth.Nature communications · 2021Article
- Limiting DNA polymerase delta alters replication dynamics and leads to a dependence on checkpoint activation and recombination-mediated DNA repair.PLoS genetics · 2021Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Accurate DNA synthesis by the replicative DNA polymerases alpha, delta, and epsilon is critical for genome stability in eukaryotes. In humans, over 20 SNPs were reported that result in amino-acid changes in Poldelta or Polepsilon. In addition, Poldelta variants were found in colon-cancer cell lines and in sporadic colorectal carcinomas. Using the yeast-model system, we examined the functional consequences of two cancer-associated Poldelta mutations and four polymorphisms affecting well-conserved regions of Poldelta or Polepsilon. We show that the R696W substitution in Poldelta (analog of the R689W change in the human cancer-cell line DLD-1) is lethal in haploid and homozygous diploid yeast. The cell death results from a catastrophic increase in spontaneous mutagenesis attributed to low-fidelity DNA synthesis by Poldelta-R696W. Heterozygotes survive, and the mutation rate depends on the relative expression level of wild-type versus mutant alleles. Based on these observations, we propose that the mutation rate in heterozygous human cells could be regulated by transient changes in gene expression leading to a temporary excess of Poldelta-R689W. The similarities between the mutational spectra of the yeast strains producing Poldelta-R696W and DLD-1 cells suggest that the altered Poldelta could be responsible for a significant proportion of spontaneous mutations in this cancer cell line. These results suggest that the highly error-prone Poldelta-R689W could contribute to cancer initiation and/or progression in humans.
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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.