Dihydropyrimidinase protects from DNA replication stress caused by cytotoxic metabolites - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Nucleic Acids Research Année : 2020

Dihydropyrimidinase protects from DNA replication stress caused by cytotoxic metabolites

J. Basbous
Antoine Aze
  • Fonction : Auteur
  • PersonId : 1309768
  • IdHAL : antoine-aze
Cyril Ribeyre
Baek Kim
Jérôme Moreaux
Marcel Méchali
  • Fonction : Auteur
  • PersonId : 912051
Angelos Constantinou

Résumé

Imbalance in the level of the pyrimidine degradation products dihydrouracil and dihydrothymine is associated with cellular transformation and cancer progression. Dihydropyrimidines are degraded by dihy-dropyrimidinase (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 di-hydropyrimidines induces the formation of DNA-protein crosslinks (DPCs) and causes DNA replication and transcriptional stress. We used Xenopus egg extracts to recapitulate DNA replication in vitro. We found that dihydropyrimidines interfere directly with the replication of both plasmid and chromo-somal 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.
Fichier principal
Vignette du fichier
Dihydropyrimidinase protects from DNA replicationstress caused by cytotoxic metabolites.pdf (4.71 Mo) Télécharger le fichier
Supplementary Figures captions.pdf (419.47 Ko) Télécharger le fichier
Supplementary Figures.pdf (2.2 Mo) Télécharger le fichier
Origine : Publication financée par une institution

Dates et versions

hal-02556387 , version 1 (06-07-2020)

Licence

Paternité - Pas d'utilisation commerciale

Identifiants

Citer

J. Basbous, Antoine Aze, Laurent Chaloin, Rana Lebdy, Dana Hodroj, et al.. Dihydropyrimidinase protects from DNA replication stress caused by cytotoxic metabolites. Nucleic Acids Research, 2020, 48 (4), pp.1886-1904. ⟨10.1093/nar/gkz1162⟩. ⟨hal-02556387⟩
82 Consultations
177 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More