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Dihydropyrimidinase protects from DNA replication stress caused by cytotoxic metabolites.

Published on Feb 28, 2020in Nucleic Acids Research11.147
· DOI :10.1093/NAR/GKZ1162
Jihane Basbous5
Estimated H-index: 5
(University of Montpellier),
Antoine Aze3
Estimated H-index: 3
(University of Montpellier)
+ 11 AuthorsAngelos Constantinou10
Estimated H-index: 10
(University of Montpellier)
Abstract
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.
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References87
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#1Nicolai B. Larsen (UCPH: University of Copenhagen)H-Index: 10
#2Alan O. Gao (UCPH: University of Copenhagen)H-Index: 2
Last. Julien P. Duxin (UCPH: University of Copenhagen)H-Index: 10
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Summary DNA-protein crosslinks (DPCs) are bulky lesions that interfere with DNA metabolism and therefore threaten genomic integrity. Recent studies implicate the metalloprotease SPRTN in S phase removal of DPCs, but how SPRTN is targeted to DPCs during DNA replication is unknown. Using Xenopus egg extracts that recapitulate replication-coupled DPC proteolysis, we show that DPCs can be degraded by SPRTN or the proteasome, which act as independent DPC proteases. Proteasome recruitment requires DPC...
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#1Justin L. Sparks (Harvard University)H-Index: 8
#2Gheorghe Chistol (Harvard University)H-Index: 6
Last. Johannes C. Walter (Harvard University)H-Index: 53
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Summary Covalent DNA-protein cross-links (DPCs) impede replication fork progression and threaten genome integrity. Using Xenopus egg extracts, we previously showed that replication fork collision with DPCs causes their proteolysis, followed by translesion DNA synthesis. We show here that when DPC proteolysis is blocked, the replicative DNA helicase CMG (CDC45, MCM2-7, GINS), which travels on the leading strand template, bypasses an intact leading strand DPC. Single-molecule imaging reveals that ...
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#1Jihane Basbous (CNRS: Centre national de la recherche scientifique)H-Index: 11
#2Angelos Constantinou (CNRS: Centre national de la recherche scientifique)H-Index: 10
AbstractFANCM is named after Fanconi anemia (FA) complement group M. The clinical symptoms of FA include congenital abnormalities, pancytopenia, and cancer proneness. However, recent studies reveal...
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#1Ramhari Kumbhar (CNRS: Centre national de la recherche scientifique)H-Index: 2
#2Sophie Vidal-Eychenié (CNRS: Centre national de la recherche scientifique)H-Index: 3
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The DNA damage response (DDR) ensures cellular adaptation to genotoxic insults. In the crowded environment of the nucleus, the assembly of productive DDR complexes requires multiple protein modifications. How the apical E1 ubiquitin activation enzyme UBA1 integrates spatially and temporally in the DDR remains elusive. Using a human cell-free system, we show that poly(ADP-ribose) polymerase 1 promotes the recruitment of UBA1 to DNA. We find that the association of UBA1 with poly(ADP-ribosyl)ated ...
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Mutations in genes involved in Fanconi anemia (FA)/BRCA DNA repair pathway cause cancer susceptibility diseases including familial breast cancer and Fanconi anemia (FA). A single FA patient with biallelic FANCM mutations was reported in 2005 but concurrent FANCA pathogenic mutations precluded assignment of FANCM as an FA gene. Here we report three individuals with biallelic FANCM truncating mutations who developed early-onset cancer and toxicity to chemotherapy but did not present congenital mal...
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#1Irene CatucciH-Index: 9
#2Ana OsorioH-Index: 46
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PurposeMonoallelic germ-line mutations in the BRCA1/FANCS, BRCA2/FANCD1 and PALB2/FANCN genes confer high risk of breast cancer. Biallelic mutations in these genes cause Fanconi anemia (FA), characterized by malformations, bone marrow failure, chromosome fragility, and cancer predisposition (BRCA2/FANCD1 and PALB2/FANCN), or an FA-like disease presenting a phenotype similar to FA but without bone marrow failure (BRCA1/FANCS). FANCM monoallelic mutations have been reported as moderate risk factor...
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Oncogene activation results in firing of ectopic origins of replication within transcribed genes, resulting in replication stress and genome instability.
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#1Antoine Aze (University of Montpellier)H-Index: 2
#2Michalis Fragkos (University of Montpellier)H-Index: 1
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Upon fertilisation, the sperm pronucleus acquires the competence to replicate the genome through a cascade of events that link chromatin remodelling to nuclear envelope formation. The factors involved have been partially identified and are poorly characterised. Here, using Xenopus laevis egg extracts we show that RNAs are required for proper nuclear envelope assembly following sperm DNA decondensation. Although chromatin remodelling and pre-replication complex formation occur normally, RNA-deple...
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#1Guido Neidhardt (University of Cologne)H-Index: 7
#2Jan Hauke (University of Cologne)H-Index: 23
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Importance Germline mutations in established moderately or highly penetrant risk genes for breast cancer (BC) and/or ovarian cancer (OC), including BRCA1 and BRCA2 , explain fewer than half of all familial BC and/or OC cases. Based on the genotyping of 2 loss-of-function (LoF) variants c.5101C>T (p.GIn1701Ter [rs147021911]) and c.5791C>T (p.Arg1931Ter [rs144567652]), the FANCM gene has been suggested as a novel BC predisposition gene, while the analysis of the entire coding region of the FANCM g...
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Dihydromyricetin is a flavonoid isolated from Ampelopsis grossedentata, which is traditionally used in China. Dihydromyricetin exhibits health-benefiting activities with minimum adverse effects. Dihydromyricetin has been demonstrated to show antioxidative, anti-inflammatory, anticancer, antimicrobial, cell death-mediating, and lipid and glucose metabolism-regulatory activities. Dihydromyricetin may scavenge ROS to protect against oxidative stress or potentiate ROS generation to counteract cancer...
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