ArticleCell death & disease2014
Uracil DNA glycosylase (UNG) loss enhances DNA double strand break formation in human cancer cells exposed to pemetrexed.
Article in Cell death & disease, 2014. 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, 47 citations in OpenAlex.
- Silencing Uracil-DNA glycosylase inhibits colorectal cancer progression.Cancer cell international · 2026Article
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- Ablating UNG activity in a mouse model inhibits colorectal cancer growth by increasing tumor immunogenicity.JCI insight · 2025Article
- A Thiopurine-like Mutagenic Process Defines TGCT Subtypes.bioRxiv : the preprint server for biology · 2025Article
- Cytotoxic mechanisms of pemetrexed and HDAC inhibition in non-small cell lung cancer cells involving ribonucleotides in DNA.Scientific reports · 2025Article
- Convenient syntheses of isotopically labeled pyrimidine 2'-deoxynucleosides and their 5-hydroxy oxidation products.Nucleosides, nucleotides & nucleic acids · 2025Article
- Binding Pattern and Structural Interactome of the Anticancer Drug 5-Fluorouracil: A Critical Review.International journal of molecular sciences · 2024Review
- 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
- Development of 1-(4-(Substituted)piperazin-1-yl)-2-((2-((4-methoxybenzyl)thio)pyrimidin-4-yl)oxy)ethanones That Target Poly (ADP-Ribose) Polymerase in Human Breast Cancer Cells.Molecules (Basel, Switzerland) · 2022Article
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- A New Class of Uracil-DNA Glycosylase Inhibitors Active against Human and Vaccinia Virus Enzyme.Molecules (Basel, Switzerland) · 2021Article
- Combinatorial Effect of PLK1 Inhibition with Temozolomide and Radiation in Glioblastoma.Cancers · 2021Article
- An effective human uracil-DNA glycosylase inhibitor targets the open pre-catalytic active site conformation.Progress in biophysics and molecular biology · 2021Article
- 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
- A possible link to uracil DNA glycosylase in the synergistic action of HDAC inhibitors and thymidylate synthase inhibitors.Journal of translational medicine · 2020Article
- Non-muscle invasive bladder cancer tissues have increased base excision repair capacity.Scientific reports · 2020Article
- The Roles of Mitochondrial Folate Metabolism in Supporting Mitochondrial DNA Synthesis, Oxidative Phosphorylation, and Cellular Function.Current developments in nutrition · 2020Article
- Genome-wide alterations of uracil distribution patterns in human DNA upon chemotherapeutic treatments.eLife · 2020Article
- Inhibitors of DNA Glycosylases as Prospective Drugs.International journal of molecular sciences · 2020Review
Corrections and comments
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Authors and funding
4 authors at 3 institutions in 1 country.
Funding
Abstract
Misincorporation of genomic uracil and formation of DNA double strand breaks (DSBs) are known consequences of exposure to TS inhibitors such as pemetrexed. Uracil DNA glycosylase (UNG) catalyzes the excision of uracil from DNA and initiates DNA base excision repair (BER). To better define the relationship between UNG activity and pemetrexed anticancer activity, we have investigated DNA damage, DSB formation, DSB repair capacity, and replication fork stability in UNG(+/+) and UNG(-/-) cells. We report that despite identical growth rates and DSB repair capacities, UNG(-/-) cells accumulated significantly greater uracil and DSBs compared with UNG(+/+) cells when exposed to pemetrexed. ChIP-seq analysis of γ-H2AX enrichment confirmed fewer DSBs in UNG(+/+) cells. Furthermore, DSBs in UNG(+/+) and UNG(-/-) cells occur at distinct genomic loci, supporting differential mechanisms of DSB formation in UNG-competent and UNG-deficient cells. UNG(-/-) cells also showed increased evidence of replication fork instability (PCNA dispersal) when exposed to pemetrexed. Thymidine co-treatment rescues S-phase arrest in both UNG(+/+) and UNG(-/-) cells treated with IC50-level pemetrexed. However, following pemetrexed exposure, UNG(-/-) but not UNG(+/+) cells are refractory to thymidine rescue, suggesting that deficient uracil excision rather than dTTP depletion is the barrier to cell cycle progression in UNG(-/-) cells. Based on these findings we propose that pemetrexed-induced uracil misincorporation is genotoxic, contributing to replication fork instability, DSB formation and ultimately cell death.
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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.