Modulation of 5-fluorouracil metabolism by thymidine

Engelbrecht, Claes; Ljungquist, Inga; Lewan, Lillemor; Yngner, Torsten

doi:10.1016/0006-2952(84)90457-x

Cited by 22 publications

(4 citation statements)

References 10 publications

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“…We have observed significant in vivo TRMT2A-RNA crosslinking following only reasonable doses of cellular 5FU exposure in our study, which potentially has important biological implications. For example, it has been shown that in addition to inhibition of thymidylate synthase, uncharacterized RNA-mediated pathways very likely also play significant roles in the cytotoxic mechanism of 5FU (40,41). It is therefore of interest that whilst disruption of pseudouridine synthase or dihydrouridine synthase, as well as pseudouridine metabolizing enzymes in yeast leads to hypersensitivity to 5FU, disruption specifically of the TRMT2A homologue instead leads to some resistance to the compound (42).…”

Section: Discussionmentioning

confidence: 99%

FICC-Seq: a method for enzyme-specified profiling of methyl-5-uridine in cellular RNA

Carter

Emmett

Mozos

et al. 2019

Nucleic Acids Research

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Methyl-5-uridine (m5U) is one the most abundant non-canonical bases present in cellular RNA, and in yeast is found at position U54 of tRNAs where modification is catalysed by the methyltransferase Trm2. Although the mammalian enzymes that catalyse m5U formation are yet to be identified via experimental evidence, based on sequence homology to Trm2, two candidates currently exist, TRMT2A and TRMT2B. Here we developed a genome-wide single-nucleotide resolution mapping method, Fluorouracil-Induced-Catalytic-Crosslinking-Sequencing (FICC-Seq), in order to identify the relevant enzymatic targets. We demonstrate that TRMT2A is responsible for the majority of m5U present in human RNA, and that it commonly targets U54 of cytosolic tRNAs. By comparison to current methods, we show that FICC-Seq is a particularly robust method for accurate and reliable detection of relevant enzymatic target sites. Our associated finding of extensive irreversible TRMT2A-tRNA crosslinking in vivo following 5-Fluorouracil exposure is also intriguing, as it suggests a tangible mechanism for a previously suspected RNA-dependent route of Fluorouracil-mediated cytotoxicity.

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Section: Discussionmentioning

confidence: 99%

FICC-Seq: a method for enzyme-specified profiling of methyl-5-uridine in cellular RNA

Carter

Emmett

Mozos

et al. 2019

Nucleic Acids Research

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“…Given that 5-FU can be readily converted into 5-fluorouridine triphosphate (5-FUTP), a ribonucleotide analog that can be incorporated into RNAs, it has been proposed that 5-FU may directly affect various aspects of gene regulation mediated by RNA, including pre-messenger RNA (mRNA) splicing, pre-ribosomal RNA (rRNA) processing and protein synthesis [ 13 , 14 , 15 , 16 ]. Indeed, significant correlations exist between 5-FU incorporation into RNA and the loss of clonogenic potential in human colon and breast cancer cell lines [ 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

5-Fluorouracil Treatment Alters the Efficiency of Translational Recoding

Karijolich

Yingzhen

et al. 2017

Genes

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5-fluorouracil (5-FU) is a chemotherapeutic agent that has been extensively studied since its initial development in the 1950s. It has been suggested that the mechanism of action of 5-FU involves both DNA- and RNA-directed processes, but this has remained controversial. In this study, using a series of in vivo reporter constructs capable of measuring translational recoding, we demonstrate that cells exposed to 5-FU display a reduced capacity to engage in a variety of translational recoding events, including +1 programmed frameshifting (PRF) and −1 PRF. In addition, 5-FU-treated cells are much less accurate at stop codon recognition, resulting in a significant increase in stop codon-readthrough. Remarkably, while the efficiency of cap-dependent translation appears to be unaffected by 5-FU, 5-FU-treated cells display a decreased ability to initiate cap-independent translation. We further show that knockdown of thymidylate synthase, an enzyme believed to be at the center of 5-FU-induced DNA damage, has no effect on the observed alterations in translational recoding. On the other hand, ribosomal RNA (rRNA) pseudouridylation, which plays an important role in translational recoding, is significantly inhibited. Taken together, our results suggest that the observed effect of 5-FU on recoding is an RNA-directed effect. Our results are the first to show definitely and quantitatively that translational recoding is affected by exposure to 5-FU. Thus, it is possible that a substantial portion of 5-FU cytotoxicity might possibly be the result of alterations in translational recoding efficiency.

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“…However, there is growing evidence that 5FU cytotoxicity may mainly be attributable to the impairment of RNA processing pathways. Accordingly, several experiments have shown that uridine, but not thymidine, relieved the cytotoxic and apoptotic effects of 5FU [1], [6]. 5FU-containing RNA has been shown to interfere with normal processing and maturation of rRNA, tRNA, and mRNA precursors [1], [4], [7]–[9].…”

Section: Introductionmentioning

confidence: 99%

New Insights into the RNA-Based Mechanism of Action of the Anticancer Drug 5′-Fluorouracil in Eukaryotic Cells

et al. 2013

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5-Fluorouracil (5FU) is a chemotherapeutic drug widely used in treating a range of advanced, solid tumours and, in particular, colorectal cancer. Here, we used high-density tiling DNA microarray technology to obtain the specific transcriptome-wide response induced by 5FU in the eukaryotic model Schizosaccharomyces pombe. This approach combined with real-time quantitative PCR analysis allowed us to detect splicing defects of a significant number of intron-containing mRNA, in addition to identify some rRNA and tRNA processing defects after 5FU treatment. Interestingly, our studies also revealed that 5FU specifically induced the expression of certain genes implicated in the processing of mRNA, tRNA and rRNA precursors, and in the post-transcriptional modification of uracil residues in RNA. The transcription of several tRNA genes was also significantly induced after drug exposure. These transcriptional changes might represent a cellular response mechanism to counteract 5FU damage since deletion strains for some of these up-regulated genes were hypersensitive to 5FU. Moreover, most of these RNA processing genes have human orthologs that participate in conserved pathways, suggesting that they could be novel targets to improve the efficacy of 5FU-based treatments.

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Modulation of 5-fluorouracil metabolism by thymidine

Cited by 22 publications

References 10 publications

FICC-Seq: a method for enzyme-specified profiling of methyl-5-uridine in cellular RNA

FICC-Seq: a method for enzyme-specified profiling of methyl-5-uridine in cellular RNA

5-Fluorouracil Treatment Alters the Efficiency of Translational Recoding

New Insights into the RNA-Based Mechanism of Action of the Anticancer Drug 5′-Fluorouracil in Eukaryotic Cells

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