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Nucleic Acids Res 2020 Feb 28;484:1886-1904. doi: 10.1093/nar/gkz1162.
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Dihydropyrimidinase protects from DNA replication stress caused by cytotoxic metabolites.

Basbous J , Aze A , Chaloin L , Lebdy R , Hodroj D , Ribeyre C , Larroque M , Shepard C , Kim B , Pruvost A , Moreaux J , Maiorano D , Mechali M , Constantinou A .

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.

PubMed ID: 31853544
PMC ID: PMC7038975
Article link: Nucleic Acids Res
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: dpys eif3a fanca fancd2 fancm gmnn
GO keywords: dihydropyrimidinase activity [+]

Article Images: [+] show captions
References [+] :
Adamson, A genome-wide homologous recombination screen identifies the RNA-binding protein RBMX as a component of the DNA-damage response. 2012, Pubmed