Ribosome quality control mitigates the cytotoxicity of ribosome collisions induced by 5-Fluorouracil

Susanta Chatterjee, Parisa Naeli, Okan Onar, Nicole Simms, Aitor Garzia, Angela Hackett, Kelsey Coyle, Patric Harris Snell, Tom McGirr, Tanvi Nitin Sawant, Kexin Dang, Zornitsa Vasileva Stoichkova, Yumna Azam, Mark P Saunders, Michael Braun, Tommy Alain, Thomas Tuschl, Simon S McDade, Daniel B Longley, Christos G GkogkasColin Adrain, John R P Knight, Seyed Mehdi Jafarnejad

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Abstract

Ribosome quality control (RQC) resolves collided ribosomes, thus preventing their cytotoxic effects. The chemotherapeutic agent 5-Fluorouracil (5FU) is best known for its misincorporation into DNA and inhibition of thymidylate synthase. However, while a major determinant of 5FU’s anticancer activity is its misincorporation into RNAs, the mechanisms by which cancer cells overcome the RNA-dependent 5FU toxicity remain ill-defined. Here, we report a role for RQC in mitigating the cytotoxic effects of 5FU. We show that 5FU treatment results in rapid induction of the mTOR signalling pathway, enhanced rate of mRNA translation initiation, and increased ribosome collisions. Consistently, a defective RQC exacerbates the 5FU-induced cell death, which is mitigated by blocking mTOR pathway or mRNA translation initiation. Furthermore, 5FU treatment enhances the expression of the key RQC factors ZNF598 and GIGYF2 via an mTOR-dependent post-translational mechanism. This adaptation likely mitigates the cytotoxic consequences of increased ribosome collisions upon 5FU treatment.

Original languageEnglish
Article numbergkae849
Number of pages15
JournalNucleic Acids Research
Early online date01 Oct 2024
DOIs
Publication statusEarly online date - 01 Oct 2024

Keywords

  • Ribosome quality control
  • cytotoxicity
  • ribosome collisions
  • 5-Fluorouracil

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