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Datum
2024-06-10Schlagwort
570 Biowissenschaften, Biologie Transfer-RNSSaccharomyces cerevisiaeFluoropyrimidineCytotoxizitätBioaktive VerbindungenMetadata
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Aufsatz
LOEWE (Landes-Offensive zur Entwicklung Wissenschaftlich-ökonomischer Exzellenz) [LOEWE/5/A001/519/06/00.002(0002)/E02 to R.K.]; DFG (Deutsche Forschungsgemeinschaft) Priority Program SPP1784 ‘Chemical Biology of Native Nucleic Acid Modifications’ [SCHA750/20 to R.S., KL2937/1 to R.K., HE3397/14-2 to M.H.]; Additional support of R.K. and R.S. by the DFG Research Training Group ‘multiscale clocks’ [448909517/GRK 2749] as well as support of M.H. by the DFG [TP C03 in TRR 319; Project-ID 439669440].
Fluoropyrimidines trigger decay of hypomodified tRNA in yeast
Zusammenfassung
Therapeutic fluoropyrimidines 5-fluorouracil (5-FU) and 5-fluorocytosine (5-FC) are in long use for treatment of human cancers and severe invasive fungal infections, respectively. 5-Fluorouridine triphosphate represents a bioactive metabolite of both drugs and is incorporated into target cells’ RNA. Here we use the model fungus Saccharomyces cerevisiae to define fluorinated tRNA as a key mediator of 5-FU and 5-FC cytotoxicity when specific tRNA methylations are absent. tRNA methylation deficiency caused by loss of Trm4 and Trm8 was previously shown to trigger an RNA quality control mechanism resulting in partial destabilization of hypomodified tRNAⱽᵃˡAAC. We demonstrate that, following incorporation into tRNA, fluoropyrimidines strongly enhance degradation of yeast tRNAⱽᵃˡAAC lacking Trm4 and Trm8 dependent methylations. At elevated temperature, such effect occurs already in absence of Trm8 alone. Genetic approaches and quantification of tRNA modification levels reveal that enhanced fluoropyrimidine cytotoxicity results from additional, drug induced uridine modification loss and activation of tRNAⱽᵃˡAAC decay involving the exonuclease Xrn1. These results suggest that inhibition of tRNA methylation may be exploited to boost therapeutic efficiency of 5-FU and 5-FC.
Zitierform
In: Nucleic Acids Research Volume 52 / Issue 10 (2024-06-10) , S. 5841-5851 ; eissn:1362-4962Förderhinweis
Gefördert durch den Publikationsfonds der Universität KasselLOEWE (Landes-Offensive zur Entwicklung Wissenschaftlich-ökonomischer Exzellenz) [LOEWE/5/A001/519/06/00.002(0002)/E02 to R.K.]; DFG (Deutsche Forschungsgemeinschaft) Priority Program SPP1784 ‘Chemical Biology of Native Nucleic Acid Modifications’ [SCHA750/20 to R.S., KL2937/1 to R.K., HE3397/14-2 to M.H.]; Additional support of R.K. and R.S. by the DFG Research Training Group ‘multiscale clocks’ [448909517/GRK 2749] as well as support of M.H. by the DFG [TP C03 in TRR 319; Project-ID 439669440].
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@article{doi:10.17170/kobra-2024062010369,
author={Görlitz, Katharina and Bessler, Larissa and Helm, Mark and Schaffrath, Raffael and Klassen, Roland},
title={Fluoropyrimidines trigger decay of hypomodified tRNA in yeast},
journal={Nucleic Acids Research},
year={2024}
}
0500 Oax 0501 Text $btxt$2rdacontent 0502 Computermedien $bc$2rdacarrier 1100 2024$n2024 1500 1/eng 2050 ##0##http://hdl.handle.net/123456789/15874 3000 Görlitz, Katharina 3010 Bessler, Larissa 3010 Helm, Mark 3010 Schaffrath, Raffael 3010 Klassen, Roland 4000 Fluoropyrimidines trigger decay of hypomodified tRNA in yeast / Görlitz, Katharina 4030 4060 Online-Ressource 4085 ##0##=u http://nbn-resolving.de/http://hdl.handle.net/123456789/15874=x R 4204 \$dAufsatz 4170 5550 {{Transfer-RNS}} 5550 {{Saccharomyces cerevisiae}} 5550 {{Fluoropyrimidine}} 5550 {{Cytotoxizität}} 5550 {{Bioaktive Verbindungen}} 7136 ##0##http://hdl.handle.net/123456789/15874
2024-06-21T13:56:36Z 2024-06-21T13:56:36Z 2024-06-10 doi:10.17170/kobra-2024062010369 http://hdl.handle.net/123456789/15874 Gefördert durch den Publikationsfonds der Universität Kassel LOEWE (Landes-Offensive zur Entwicklung Wissenschaftlich-ökonomischer Exzellenz) [LOEWE/5/A001/519/06/00.002(0002)/E02 to R.K.]; DFG (Deutsche Forschungsgemeinschaft) Priority Program SPP1784 ‘Chemical Biology of Native Nucleic Acid Modifications’ [SCHA750/20 to R.S., KL2937/1 to R.K., HE3397/14-2 to M.H.]; Additional support of R.K. and R.S. by the DFG Research Training Group ‘multiscale clocks’ [448909517/GRK 2749] as well as support of M.H. by the DFG [TP C03 in TRR 319; Project-ID 439669440]. eng Namensnennung-Nicht-kommerziell 4.0 International http://creativecommons.org/licenses/by-nc/4.0/ 570 Fluoropyrimidines trigger decay of hypomodified tRNA in yeast Aufsatz Therapeutic fluoropyrimidines 5-fluorouracil (5-FU) and 5-fluorocytosine (5-FC) are in long use for treatment of human cancers and severe invasive fungal infections, respectively. 5-Fluorouridine triphosphate represents a bioactive metabolite of both drugs and is incorporated into target cells’ RNA. Here we use the model fungus Saccharomyces cerevisiae to define fluorinated tRNA as a key mediator of 5-FU and 5-FC cytotoxicity when specific tRNA methylations are absent. tRNA methylation deficiency caused by loss of Trm4 and Trm8 was previously shown to trigger an RNA quality control mechanism resulting in partial destabilization of hypomodified tRNAⱽᵃˡAAC. We demonstrate that, following incorporation into tRNA, fluoropyrimidines strongly enhance degradation of yeast tRNAⱽᵃˡAAC lacking Trm4 and Trm8 dependent methylations. At elevated temperature, such effect occurs already in absence of Trm8 alone. Genetic approaches and quantification of tRNA modification levels reveal that enhanced fluoropyrimidine cytotoxicity results from additional, drug induced uridine modification loss and activation of tRNAⱽᵃˡAAC decay involving the exonuclease Xrn1. These results suggest that inhibition of tRNA methylation may be exploited to boost therapeutic efficiency of 5-FU and 5-FC. open access Görlitz, Katharina Bessler, Larissa Helm, Mark Schaffrath, Raffael Klassen, Roland doi:10.1093/nar/gkae341 Project-ID 439669440 Transfer-RNS Saccharomyces cerevisiae Fluoropyrimidine Cytotoxizität Bioaktive Verbindungen publishedVersion eissn:1362-4962 Issue 10 Nucleic Acids Research 5841-5851 Volume 52 false
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