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Alteration of ribosome function upon 5-fluorouracil treatment favors cancer cell drug-tolerance
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National audience. Mechanisms of drug-tolerance remain poorly understood and have been linked to genomic but alsoto non-genomic processes. 5-fluorouracil (5-FU), the most widely used che- motherapy in oncology isassociated with resistance. While prescribed as an inhibitor of DNA replication, 5-FU alters all RNApathways.Here, we show that 5-FU treatment leads to the production of fluorinated ribosomes exhibitingaltered translational activities. 5-FU is incor- porated into ribosomal RNAs of mature ribosomesin cancer cell lines, colorectal xenografts, and human tumors. Fluorinated ribosomes appear to befunctional, yet, they display a selective translational activity towards mRNAs depending on the natureof their 5′ -untranslated region. The translational selectivity was determined by bioinformatic analysisof deep sequencing data that combine RNA-seq of both the cytosomal and polysomal fractions ofmRNAs.As a result, we find that sustained translation of IGF-1R mRNA, which encodes one of the mostpotent cell survival effectors, promotes the survival of 5-FU-treated colorectal cancer cells. Alto-gether, our results demonstrate that man-made fluorinated ribosomes favor the drug-tolerant cellularphenotype by promoting translation of survival genes.This work has been published in 2022 in Nature Communications [1].
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