Cargando…

Dihydropyrimidinase protects from DNA replication stress caused by cytotoxic metabolites

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 corr...

Descripción completa

Detalles Bibliográficos
Autores principales: Basbous, Jihane, Aze, Antoine, Chaloin, Laurent, Lebdy, Rana, Hodroj, Dana, Ribeyre, Cyril, Larroque, Marion, Shepard, Caitlin, Kim, Baek, Pruvost, Alain, Moreaux, Jérôme, Maiorano, Domenico, Mechali, Marcel, Constantinou, Angelos
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7038975/
https://www.ncbi.nlm.nih.gov/pubmed/31853544
http://dx.doi.org/10.1093/nar/gkz1162
_version_ 1783500741467439104
author Basbous, Jihane
Aze, Antoine
Chaloin, Laurent
Lebdy, Rana
Hodroj, Dana
Ribeyre, Cyril
Larroque, Marion
Shepard, Caitlin
Kim, Baek
Pruvost, Alain
Moreaux, Jérôme
Maiorano, Domenico
Mechali, Marcel
Constantinou, Angelos
author_facet Basbous, Jihane
Aze, Antoine
Chaloin, Laurent
Lebdy, Rana
Hodroj, Dana
Ribeyre, Cyril
Larroque, Marion
Shepard, Caitlin
Kim, Baek
Pruvost, Alain
Moreaux, Jérôme
Maiorano, Domenico
Mechali, Marcel
Constantinou, Angelos
author_sort Basbous, Jihane
collection PubMed
description 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.
format Online
Article
Text
id pubmed-7038975
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Oxford University Press
record_format MEDLINE/PubMed
spelling pubmed-70389752020-03-02 Dihydropyrimidinase protects from DNA replication stress caused by cytotoxic metabolites Basbous, Jihane Aze, Antoine Chaloin, Laurent Lebdy, Rana Hodroj, Dana Ribeyre, Cyril Larroque, Marion Shepard, Caitlin Kim, Baek Pruvost, Alain Moreaux, Jérôme Maiorano, Domenico Mechali, Marcel Constantinou, Angelos Nucleic Acids Res Genome Integrity, Repair and Replication 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. Oxford University Press 2020-02-28 2019-12-19 /pmc/articles/PMC7038975/ /pubmed/31853544 http://dx.doi.org/10.1093/nar/gkz1162 Text en © The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Genome Integrity, Repair and Replication
Basbous, Jihane
Aze, Antoine
Chaloin, Laurent
Lebdy, Rana
Hodroj, Dana
Ribeyre, Cyril
Larroque, Marion
Shepard, Caitlin
Kim, Baek
Pruvost, Alain
Moreaux, Jérôme
Maiorano, Domenico
Mechali, Marcel
Constantinou, Angelos
Dihydropyrimidinase protects from DNA replication stress caused by cytotoxic metabolites
title Dihydropyrimidinase protects from DNA replication stress caused by cytotoxic metabolites
title_full Dihydropyrimidinase protects from DNA replication stress caused by cytotoxic metabolites
title_fullStr Dihydropyrimidinase protects from DNA replication stress caused by cytotoxic metabolites
title_full_unstemmed Dihydropyrimidinase protects from DNA replication stress caused by cytotoxic metabolites
title_short Dihydropyrimidinase protects from DNA replication stress caused by cytotoxic metabolites
title_sort dihydropyrimidinase protects from dna replication stress caused by cytotoxic metabolites
topic Genome Integrity, Repair and Replication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7038975/
https://www.ncbi.nlm.nih.gov/pubmed/31853544
http://dx.doi.org/10.1093/nar/gkz1162
work_keys_str_mv AT basbousjihane dihydropyrimidinaseprotectsfromdnareplicationstresscausedbycytotoxicmetabolites
AT azeantoine dihydropyrimidinaseprotectsfromdnareplicationstresscausedbycytotoxicmetabolites
AT chaloinlaurent dihydropyrimidinaseprotectsfromdnareplicationstresscausedbycytotoxicmetabolites
AT lebdyrana dihydropyrimidinaseprotectsfromdnareplicationstresscausedbycytotoxicmetabolites
AT hodrojdana dihydropyrimidinaseprotectsfromdnareplicationstresscausedbycytotoxicmetabolites
AT ribeyrecyril dihydropyrimidinaseprotectsfromdnareplicationstresscausedbycytotoxicmetabolites
AT larroquemarion dihydropyrimidinaseprotectsfromdnareplicationstresscausedbycytotoxicmetabolites
AT shepardcaitlin dihydropyrimidinaseprotectsfromdnareplicationstresscausedbycytotoxicmetabolites
AT kimbaek dihydropyrimidinaseprotectsfromdnareplicationstresscausedbycytotoxicmetabolites
AT pruvostalain dihydropyrimidinaseprotectsfromdnareplicationstresscausedbycytotoxicmetabolites
AT moreauxjerome dihydropyrimidinaseprotectsfromdnareplicationstresscausedbycytotoxicmetabolites
AT maioranodomenico dihydropyrimidinaseprotectsfromdnareplicationstresscausedbycytotoxicmetabolites
AT mechalimarcel dihydropyrimidinaseprotectsfromdnareplicationstresscausedbycytotoxicmetabolites
AT constantinouangelos dihydropyrimidinaseprotectsfromdnareplicationstresscausedbycytotoxicmetabolites