Patrick G. Johnston Centre for Cancer Research, Queen's University Belfast, Belfast BT7 9AE, UK.
Department of Biology, Faculty of Science, Ankara University, Ankara, Turkey.
Nucleic Acids Res. 2024 Nov 11;52(20):12534-12548. doi: 10.1093/nar/gkae849.
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.
核糖体质量控制 (RQC) 可以解决碰撞的核糖体，从而防止其产生细胞毒性作用。化疗药物 5-氟尿嘧啶 (5FU) 以其掺入 DNA 错误和胸苷酸合成酶抑制作用而闻名。然而，虽然 5FU 抗癌活性的主要决定因素是其掺入 RNA 中，但癌细胞克服 RNA 依赖性 5FU 毒性的机制仍未明确。在这里，我们报告了 RQC 在减轻 5FU 细胞毒性作用中的作用。我们发现，5FU 处理会导致 mTOR 信号通路的快速诱导，mRNA 翻译起始率的提高和核糖体碰撞的增加。一致地，RQC 缺陷会加剧 5FU 诱导的细胞死亡，而阻断 mTOR 途径或 mRNA 翻译起始可以减轻这种细胞死亡。此外，5FU 处理通过 mTOR 依赖性的翻译后机制增强了关键 RQC 因子 ZNF598 和 GIGYF2 的表达。这种适应性可能减轻了 5FU 处理后核糖体碰撞增加的细胞毒性后果。
