Fluoropyrimidines trigger decay of hypomodified tRNA in yeast
| dc.date.accessioned | 2024-06-21T13:56:36Z | |
| dc.date.available | 2024-06-21T13:56:36Z | |
| dc.date.issued | 2024-06-10 | |
| dc.identifier | doi:10.17170/kobra-2024062010369 | |
| dc.identifier.uri | http://hdl.handle.net/123456789/15874 | |
| dc.description.sponsorship | Gefördert durch den Publikationsfonds der Universität Kassel | ger |
| dc.description.sponsorship | 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 |
| dc.language.iso | eng | |
| dc.rights | Namensnennung-Nicht-kommerziell 4.0 International | * |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc/4.0/ | * |
| dc.subject.ddc | 570 | |
| dc.title | Fluoropyrimidines trigger decay of hypomodified tRNA in yeast | eng |
| dc.type | Aufsatz | |
| dcterms.abstract | 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. | eng |
| dcterms.accessRights | open access | |
| dcterms.creator | Görlitz, Katharina | |
| dcterms.creator | Bessler, Larissa | |
| dcterms.creator | Helm, Mark | |
| dcterms.creator | Schaffrath, Raffael | |
| dcterms.creator | Klassen, Roland | |
| dc.relation.doi | doi:10.1093/nar/gkae341 | |
| dc.relation.projectid | Project-ID 439669440 | ger |
| dc.subject.swd | Transfer-RNS | ger |
| dc.subject.swd | Saccharomyces cerevisiae | ger |
| dc.subject.swd | Fluoropyrimidine | ger |
| dc.subject.swd | Cytotoxizität | ger |
| dc.subject.swd | Bioaktive Verbindungen | ger |
| dc.type.version | publishedVersion | |
| dcterms.source.identifier | eissn:1362-4962 | |
| dcterms.source.issue | Issue 10 | |
| dcterms.source.journal | Nucleic Acids Research | eng |
| dcterms.source.pageinfo | 5841-5851 | |
| dcterms.source.volume | Volume 52 | |
| kup.iskup | false |
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