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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...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2020
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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 |
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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 |
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