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

Chatterjee S., Naeli P., Onar O., Simms N., Garzia A., Hackett A., ...Daha Fazla

NUCLEIC ACIDS RESEARCH, cilt.52, sa.20, ss.12534-12548, 2024 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 52 Sayı: 20
  • Basım Tarihi: 2024
  • Doi Numarası: 10.1093/nar/gkae849
  • Dergi Adı: NUCLEIC ACIDS RESEARCH
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Applied Science & Technology Source, BIOSIS, Biotechnology Research Abstracts, CAB Abstracts, Chemical Abstracts Core, Veterinary Science Database, Directory of Open Access Journals, DIALNET
  • Sayfa Sayıları: ss.12534-12548
  • Ankara Üniversitesi Adresli: Hayır

Özet

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.