Authors: Gabriel Therizols, Zeina Bash-Imam, Baptiste Panthu, Christelle Machon, Anne Vincent, Julie Ripoll, Sophie Nait-Slimane, Mounira Chalabi-Dchar, Angéline Gaucherot, Maxime Garcia, Florian Laforêts, Virginie Marcel, Jihane Boubaker-Vitre, Marie-Ambre Monet, Céline Bouclier, Christophe Vanbelle, Guillaume Souahlia, Elise Berthel, Marie Alexandra Albaret, Hichem C. Mertani, Michel Prudhomme, Martin Bertrand, Alexandre David, Jean-Christophe Saurin, Philippe Bouvet, Eric Rivals, Théophile Ohlmann, Jérôme Guitton, Nicole Dalla Venezia, Julie Pannequin, Frédéric Catez, Jean-Jacques Diaz
Published: 2022-01-10
DOI: 10.1038/s41467-021-27847-8
Source: Full article
AbstractMechanisms of drug-tolerance remain poorly understood and have been linked to genomic but also to non-genomic processes. 5-fluorouracil (5-FU), the most widely used chemotherapy in oncology is associated with resistance. While prescribed as an inhibitor of DNA replication, 5-FU alters all RNA pathways. Here, we show that 5-FU treatment leads to the production of fluorinated ribosomes exhibiting altered translational activities. 5-FU is incorporated into ribosomal RNAs of mature ribosomes in cancer cell lines, colorectal xenografts, and human tumors. Fluorinated ribosomes appear to be functional, yet, they display a selective translational activity towards mRNAs depending on the nature of their 5′-untranslated region. As a result, we find that sustained translation ofIGF-1RmRNA, which encodes one of the most potent cell survival effectors, promotes the survival of 5-FU-treated colorectal cancer cells. Altogether, our results demonstrate that “man-made” fluorinated ribosomes favor the drug-tolerant cellular phenotype by promoting translation of survival genes.