Dihydropyrimidinase protects from DNA replication stress caused by cytotoxic metabolites

Metabolic alterations support cellular transformation. Noticeably, cellular transformation and cancer progression is associated with accumulation of dihydrouracil and dihydrothymine. However, it remains elusive how dihydropyrimidine metabolites affect cellular phenotypes. Dihydropyrimidines are degr...

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Bibliographic Details
Published inbioRxiv
Main Authors Basbous, Jihane, Aze, Antoine, Chaloin, Laurent, Rana Lebdy, Hodroj, Dana, Ribeyre, Cyril, Larroque, Marion, Shepard, Caitlin, Baek, Kim, Pruvost, Alain, Moreaux, Jerome, Maiorano, Domenico, Mechali, Marcel, Constantinou, Angelos
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 18.09.2018
Subjects
Cytotoxicity
Deoxyribonucleic acid
Dihydropyrimidinase
DNA
DNA biosynthesis
DNA-directed DNA polymerase
Flavonoids
Genetic transformation
Metabolites
p53 Protein
Phenotypes
Replication
Solid tumors
Therapeutic targets
Transcription
Tumors
Zinc metalloenzyme
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Summary:Metabolic alterations support cellular transformation. Noticeably, cellular transformation and cancer progression is associated with accumulation of dihydrouracil and dihydrothymine. However, it remains elusive how dihydropyrimidine metabolites affect cellular phenotypes. Dihydropyrimidines are degraded by dihydropyrimidinase (DHP). This zinc metalloenzyme is upregulated in solid tumors but not in the corresponding normal tissues. Here we show that DHP silencing in transformed cell lines is cytotoxic. Increasing the level of dihydropyrimidines inhibited DNA replication and transcription. It induced replication stress signaling by ATR and p53 stabilization. Remarkably, cells lacking DHP accumulated DNA-protein crosslinks (DPCs). Among DPCs, covalently trapped translesion DNA polymerase eta contributed to the cytotoxicity of dihydropyrimidines. Furthermore, we show that the plant flavonoid dihydromyricetin inhibits the activity of recombinant human DHP. Cellular treatment with dihydromyricetin triggered DPCs-dependent DNA replication stress. This study defines dihydropyrimidines as potentially cytotoxic metabolites that may offer an opportunity for therapeutic-targeting of DHP activity in solid tumors.
DOI:10.1101/420893