ArticleMolecular pharmacology2016
Genomically Incorporated 5-Fluorouracil that Escapes UNG-Initiated Base Excision Repair Blocks DNA Replication and Activates Homologous Recombination.
Article in Molecular pharmacology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 54 citations in OpenAlex.
- Adjuvant capecitabine-containing chemotherapy benefit and homologous recombination deficiency in early-stage triple-negative breast cancer patients.British journal of cancer · 2022Trial
- Efficacy of Hepatic Artery Infusion Chemotherapy Combined With Regorafenib and Sintilimab Versus Regorafenib Alone in MSS/pMMR Colorectal Cancer Liver Metastases After Second-Line Treatment Failure.Cancer medicine · 2026Article
- Article
- Biopolymeric Films from the White Rind of Watermelon (ACS omega · 2025Article
- Ablating UNG activity in a mouse model inhibits colorectal cancer growth by increasing tumor immunogenicity.JCI insight · 2025Article
- Structural and Functional Insights into UDGs.Protein and peptide letters · 2025Review
- REV3 promotes cellular tolerance to 5-fluorodeoxyuridine by activating translesion DNA synthesis and intra-S checkpoint.PLoS genetics · 2024Article
- The epigenetic modifier HDAC2 and the checkpoint kinase ATM determine the responses of microsatellite instable colorectal cancer cells to 5-fluorouracil.Cell biology and toxicology · 2023Article
- Replication Protein A Enhances Kinetics of Uracil DNA Glycosylase on ssDNA and Across DNA Junctions: Explored with a DNA Repair Complex Produced with SpyCatcher/SpyTag Ligation.Chembiochem : a European journal of chemical biology · 2023Article
- Computational analysis of 5-fluorouracil anti-tumor activity in colon cancer using a mechanistic pharmacokinetic/pharmacodynamic model.PLoS computational biology · 2022Article
- Review
- Molecular Pathogenesis of Colorectal Cancer with an Emphasis on Recent Advances in Biomarkers, as Well as Nanotechnology-Based Diagnostic and Therapeutic Approaches.Nanomaterials (Basel, Switzerland) · 2022Review
- Inhibition of Human Uracil DNA Glycosylase Sensitizes a Large Fraction of Colorectal Cancer Cells to 5-Fluorodeoxyuridine and Raltitrexed but Not Fluorouracil.Molecular pharmacology · 2021Article
- Targeting nucleotide metabolism enhances the efficacy of anthracyclines and anti-metabolites in triple-negative breast cancer.NPJ breast cancer · 2021Article
- dUTPase inhibition confers susceptibility to a thymidylate synthase inhibitor in DNA-repair-defective human cancer cells.Cancer science · 2021Article
- Base excision repair and its implications to cancer therapy.Essays in biochemistry · 2020Review
- A possible link to uracil DNA glycosylase in the synergistic action of HDAC inhibitors and thymidylate synthase inhibitors.Journal of translational medicine · 2020Article
- Genome-wide alterations of uracil distribution patterns in human DNA upon chemotherapeutic treatments.eLife · 2020Article
- A robust photoluminescence screening assay identifies uracil-DNA glycosylase inhibitors against prostate cancer.Chemical science · 2020Article
- 5-Fluorouracil treatment induces characteristic T>G mutations in human cancer.Nature communications · 2019Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
5-Fluorouracil (5-FU) and its metabolite 5-fluorodeoxyuridine (FdUrd, floxuridine) are chemotherapy agents that are converted to 5-fluorodeoxyuridine monophosphate (FdUMP) and 5-fluorodeoxyuridine triphosphate (FdUTP). FdUMP inhibits thymidylate synthase and causes the accumulation of uracil in the genome, whereas FdUTP is incorporated by DNA polymerases as 5-FU in the genome; however, it remains unclear how either genomically incorporated U or 5-FU contributes to killing. We show that depletion of the uracil DNA glycosylase (UNG) sensitizes tumor cells to FdUrd. Furthermore, we show that UNG depletion does not sensitize cells to the thymidylate synthase inhibitor (raltitrexed), which induces uracil but not 5-FU accumulation, thus indicating that genomically incorporated 5-FU plays a major role in the antineoplastic effects of FdUrd. We also show that 5-FU metabolites do not block the first round of DNA synthesis but instead arrest cells at the G1/S border when cells again attempt replication and activate homologous recombination (HR). This arrest is not due to 5-FU lesions blocking DNA polymerase δ but instead depends, in part, on the thymine DNA glycosylase. Consistent with the activation of HR repair, disruption of HR sensitized cells to FdUrd, especially when UNG was disabled. These results show that 5-FU lesions that escape UNG repair activate HR, which promotes cell survival.
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Registered trials
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