N7-methylguanosine methylation of tRNAs regulates survival to stress in cancer

Raquel García-Vílchez, Ana M. Añazco-Guenkova, Judith López, Sabine Dietmann, Mercedes Tomé, Sonia Jimeno, Mikel Azkargorta, Félix Elortza, Laura Bárcena, Monika Gonzalez-Lopez, Ana M. Aransay, Manuel A. Sánchez-Martín, Pablo Huertas, Raúl V. Durán, Sandra Blanco

Research output: Contribution to journalArticlepeer-review

Abstract

Tumour progression and therapy tolerance are highly regulated and complex processes largely dependent on the plasticity of cancer cells and their capacity to respond to stress. The higher plasticity of cancer cells highlights the need for identifying targetable molecular pathways that challenge cancer cell survival. Here, we show that N7-guanosine methylation (m7G) of tRNAs, mediated by METTL1, regulates survival to stress conditions in cancer cells. Mechanistically, we find that m7G in tRNAs protects them from stress-induced cleavage and processing into 5’ tRNA fragments. Our analyses reveal that the loss of tRNA m7G methylation activates stress response pathways, sensitising cancer cells to stress. Furthermore, we find that the loss of METTL1 reduces tumour growth and increases cytotoxic stress in vivo. Our study uncovers the role of m7G methylation of tRNAs in stress responses and highlights the potential of targeting METTL1 to sensitise cancer cells to chemotherapy.

Original languageEnglish
Pages (from-to)3169-3181
Number of pages13
JournalOncogene
Volume42
Issue number43
DOIs
StatePublished - Oct 20 2023

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