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Ribosome quality control mitigates the cytotoxicity of ribosome collisions induced by 5-fluorouracil
Chatterjee, S. Naeli, P. Onar, O. Simms, Nicole Garzia, A. Hackett, A. Coyle, K. Harris Snell, P. McGirr, T. Sawant, T. N.
Chatterjee, S.
Naeli, P.
Onar, O.
Simms, Nicole
Garzia, A.
Hackett, A.
Coyle, K.
Harris Snell, P.
McGirr, T.
Sawant, T. N.
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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.
Authors
Chatterjee, S.
Naeli, P.
Onar, O.
Simms, Nicole
Garzia, A.
Hackett, A.
Coyle, K.
Harris Snell, P.
McGirr, T.
Sawant, T. N.
Dang, Kexin
Stoichkova, Zornitsa V
Azam, Y.
Saunders, Mark P
Braun, Michael
Alain, T.
Tuschl, T.
McDade, S. S.
Longley, D. B.
Gkogkas, C. G.
Adrain, C.
Knight, John R P
Jafarnejad, S. M.
Naeli, P.
Onar, O.
Simms, Nicole
Garzia, A.
Hackett, A.
Coyle, K.
Harris Snell, P.
McGirr, T.
Sawant, T. N.
Dang, Kexin
Stoichkova, Zornitsa V
Azam, Y.
Saunders, Mark P
Braun, Michael
Alain, T.
Tuschl, T.
McDade, S. S.
Longley, D. B.
Gkogkas, C. G.
Adrain, C.
Knight, John R P
Jafarnejad, S. M.
Description
Date
2024
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Article
Citation
Chatterjee S, Naeli P, Onar O, Simms N, Garzia A, Hackett A, et al. Ribosome Quality Control mitigates the cytotoxicity of ribosome collisions induced by 5-Fluorouracil. Nucleic acids research. 2024 Nov 11;52(20):12534-48. PubMed PMID: 39351862. Pubmed Central PMCID: PMC11551743. Epub 2024/10/01. eng.