Perturbation of METTL1-mediated tRNA N7- methylguanosine modification induces senescence and aging

Yudong Fu, Fan Jiang, Xiao Zhang, Yingyi Pan, Rui Xu, Xiu Liang, Xiaofen Wu, Xingqiang Li, Kaixuan Lin, Ruona Shi, Xiaofei Zhang, Dominique Ferrandon, Jing Liu, Duanqing Pei, Jie Wang () and Tao Wang ()
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Yudong Fu: Chinese Academy of Sciences
Fan Jiang: Chinese Academy of Sciences
Xiao Zhang: Chinese Academy of Sciences
Yingyi Pan: Guangzhou Medical University
Rui Xu: Foshan maternal and children’s hospital affiliated to southern medical university
Xiu Liang: Chinese Academy of Sciences
Xiaofen Wu: Chinese Academy of Sciences
Xingqiang Li: Bioland Laboratory
Kaixuan Lin: Chinese Academy of Sciences
Ruona Shi: Chinese Academy of Sciences
Xiaofei Zhang: Chinese Academy of Sciences
Dominique Ferrandon: Guangzhou Medical University
Jing Liu: Chinese Academy of Sciences
Duanqing Pei: Westlake University
Jie Wang: Chinese Academy of Sciences
Tao Wang: Chinese Academy of Sciences

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: Abstract Cellular senescence is characterized by a decrease in protein synthesis, although the underlying processes are mostly unclear. Chemical modifications to transfer RNAs (tRNAs) frequently influence tRNA activity, which is crucial for translation. We describe how tRNA N7-methylguanosine (m7G46) methylation, catalyzed by METTL1-WDR4, regulates translation and influences senescence phenotypes. Mettl1/Wdr4 and m7G gradually diminish with senescence and aging. A decrease in METTL1 causes a reduction in tRNAs, especially those with the m7G modification, via the rapid tRNA degradation (RTD) pathway. The decreases cause ribosomes to stall at certain codons, impeding the translation of mRNA that is essential in pathways such as Wnt signaling and ribosome biogenesis. Furthermore, chronic ribosome stalling stimulates the ribotoxic and integrative stress responses, which induce senescence-associated secretory phenotype. Moreover, restoring eEF1A protein mitigates senescence phenotypes caused by METTL1 deficiency by reducing RTD. Our findings demonstrate that tRNA m7G modification is essential for preventing premature senescence and aging by enabling efficient mRNA translation.

Date: 2024
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DOI: 10.1038/s41467-024-49796-8

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