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Published January 1, 2024 | Version v1
Journal article Open

Ribosome Quality Control mitigates the cytotoxicity of ribosome collisions induced by 5-Fluorouracil

Creators

  • 1. Queens Univ Belfast, Patrick G Johnston Ctr Canc Res, Belfast BT7 9AE, North Ireland
  • 2. Univ Manchester, Div Canc Sci, Fac Biol Med & Hlth, Manchester M13 9NT, England
  • 3. Rockefeller Univ, Lab RNA Mol Biol, 1230 York Ave, New York, NY 10065 USA
  • 4. Univ Ottawa, Childrens Hosp Eastern Ontario, Res Inst, Dept Biochem Microbiol & Immunol, Ottawa, ON K1H 8L1, Canada
  • 5. Fdn Res & Technol Hellas, Biomed Res Inst, Univ Campus, Ioannina 45110, Greece

Description

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.

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