ArticleNucleic acids research2020
Dihydropyrimidinase protects from DNA replication stress caused by cytotoxic metabolites.
Article in Nucleic acids research, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 28 citations in OpenAlex.
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- Conformational Dynamics of the Active Site Loop in Dihydroorotase Highlighting the Limitations of Loop-In Structures for Inhibitor Docking.International journal of molecular sciences · 2025Article
- Bioactive Potential ofPlants (Basel, Switzerland) · 2025Article
- Urinary Metabolic Profiling During Epileptogenesis in Rat Model of Lithium-Pilocarpine-Induced Temporal Lobe Epilepsy.Biomedicines · 2025Article
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- Crystal Structure of Allantoinase from Escherichia coli BL21: A Molecular Insight into a Role of the Active Site Loops in CatalysisMolecules (Basel, Switzerland) · 2023Article
- Identification of fungal dihydrouracil-oxidase genes by expression in Saccharomyces cerevisiae.Antonie van Leeuwenhoek · 2022Article
- Cytotoxic Activities and the Allantoinase Inhibitory Effect of the Leaf Extract of the Carnivorous Pitcher PlantPlants (Basel, Switzerland) · 2022Article
- Identification of Important Genes Involved in the Sex-Differentiation Mechanism of Oriental River Prawn,Frontiers in genetics · 2022Article
- Identification of crucial genes of pyrimidine metabolism as biomarkers for gastric cancer prognosis.Cancer cell international · 2021Article
- Metabolomic Profiles of Men and Women Ischemic Stroke Patients.Diagnostics (Basel, Switzerland) · 2021Article
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- Clinical Significance of Screening Differential Metabolites in Ovarian Cancer Tissue and Ascites by LC/MS.Frontiers in pharmacology · 2021Article
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Authors and funding
14 authors at 3 institutions in 2 countries.
Funding
Abstract
Imbalance in the level of the pyrimidine degradation products dihydrouracil and dihydrothymine is associated with cellular transformation and cancer progression. Dihydropyrimidines are degraded by dihydropyrimidinase (DHP), a zinc metalloenzyme that is upregulated in solid tumors but not in the corresponding normal tissues. How dihydropyrimidine metabolites affect cellular phenotypes remains elusive. Here we show that the accumulation of dihydropyrimidines induces the formation of DNA-protein crosslinks (DPCs) and causes DNA replication and transcriptional stress. We used Xenopus egg extracts to recapitulate DNA replication invitro. We found that dihydropyrimidines interfere directly with the replication of both plasmid and chromosomal DNA. Furthermore, we show that the plant flavonoid dihydromyricetin inhibits human DHP activity. Cellular exposure to dihydromyricetin triggered DPCs-dependent DNA replication stress in cancer cells. This study defines dihydropyrimidines as potentially cytotoxic metabolites that may offer an opportunity for therapeutic-targeting of DHP activity in solid tumors.
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