ArticleCancer science2021
dUTPase inhibition confers susceptibility to a thymidylate synthase inhibitor in DNA-repair-defective human cancer cells.
Article in Cancer science, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 38 citations in OpenAlex.
- Nuclear localization of the glutaminyl-tRNA synthetase QARS reveals its role in DNA damage response in ovarian cancer.Nature communications · 2026Article
- Nucleotide salvage, genome instability, and potential therapeutic applications.Nucleic acids research · 2026Review
- Full-length inhibitor protein is the most effective to perturb human dUTPase activity.Scientific reports · 2025Article
- Convenient syntheses of isotopically labeled pyrimidine 2'-deoxynucleosides and their 5-hydroxy oxidation products.Nucleosides, nucleotides & nucleic acids · 2025Article
- MiCK: a database of gut microbial genes linked with chemoresistance in cancer patients.Database : the journal of biological databases and curation · 2024Article
- dUTP pyrophosphatases from hyperthermophilic eubacterium and archaeon: Structural and functional examinations on the suitability for PCR application.Protein science : a publication of the Protein Society · 2024Article
- 5-aminolevulinic acid photodynamic therapy protects against UVB-induced skin photoaging: A DNA-repairing mechanism involving the BER signalling pathway.Journal of cellular and molecular medicine · 2024Article
- Unprocessed genomic uracil as a source of DNA replication stress in cancer cells.Molecular cell · 2024Article
- Identification of two novel linear epitopes on the E165R protein of African swine fever virus recognized by monoclonal antibodies.Frontiers in veterinary science · 2024Article
- Hepatoprotective effect of Nobiletin against 5-fluorouracil induce hepatotoxicity.Current research in pharmacology and drug discovery · 2024Article
- Enzyme kinetics of deoxyuridine triphosphatase from Western corn rootworm.BMC research notes · 2023Article
- A semimechanistic population pharmacokinetic and pharmacodynamic model incorporating autoinduction for the dose justification of TAS-114.CPT: pharmacometrics & systems pharmacology · 2022Article
- Article
- Identification and Characterization of a Novel Epitope of ASFV-Encoded dUTPase by Monoclonal Antibodies.Viruses · 2021Article
- Viruses with U-DNA: New Avenues for Biotechnology.Viruses · 2021Review
- Detection of Genomic Uracil Patterns.International journal of molecular sciences · 2021Review
- Article
- Screening and Identification of a Novel Anti-tuberculosis Compound That Targets Deoxyuridine 5'-Triphosphate Nucleotidohydrolase.Frontiers in microbiology · 2021Article
- dUTPase inhibition confers susceptibility to a thymidylate synthase inhibitor in DNA-repair-defective human cancer cells.Cancer science · 2021Article
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Authors and funding
12 authors at 1 institution in 1 country.
Funding
Abstract
Deficiency in DNA repair proteins confers susceptibility to DNA damage, making cancer cells vulnerable to various cancer chemotherapies. 5-Fluorouracil (5-FU) is an anticancer nucleoside analog that both inhibits thymidylate synthase (TS) and causes DNA damage via the misincorporation of FdUTP and dUTP into DNA under the conditions of dTTP depletion. However, the role of the DNA damage response to its antitumor activity is still unclear. To determine which DNA repair pathway contributes to DNA damage caused by 5-FU and uracil misincorporation, we examined cancer cells treated with 2'-deoxy-5-fluorouridine (FdUrd) in the presence of TAS-114, a highly potent inhibitor of dUTPase that restricts aberrant base misincorporation. Addition of TAS-114 increased FdUTP and dUTP levels in HeLa cells and facilitated 5-FU and uracil misincorporation into DNA, but did not alter TS inhibition or 5-FU incorporation into RNA. TAS-114 showed synergistic potentiation of FdUrd cytotoxicity and caused aberrant base misincorporation, leading to DNA damage and induced cell death even after short-term exposure to FdUrd. Base excision repair (BER) and homologous recombination (HR) were found to be involved in the DNA repair of 5-FU and uracil misincorporation caused by dUTPase inhibition in genetically modified chicken DT40 cell lines and siRNA-treated HeLa cells. These results suggested that BER and HR are major pathways that protect cells from the antitumor effects of massive incorporation of 5-FU and uracil. Further, dUTPase inhibition has the potential to maximize the antitumor activity of fluoropyrimidines in cancers that are defective in BER or HR.
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