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

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  • Yudong Fu

    (Chinese Academy of Sciences
    GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre
    GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine
    University of Chinese Academy of Sciences)

  • Fan Jiang

    (Chinese Academy of Sciences
    GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre
    GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine)

  • Xiao Zhang

    (Chinese Academy of Sciences
    GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre
    GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine
    University of 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
    GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre
    GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine)

  • Xiaofen Wu

    (Chinese Academy of Sciences
    GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre
    GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine)

  • Xingqiang Li

    (Bioland Laboratory)

  • Kaixuan Lin

    (Chinese Academy of Sciences
    GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre
    GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine)

  • Ruona Shi

    (Chinese Academy of Sciences
    GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre
    GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine)

  • Xiaofei Zhang

    (Chinese Academy of Sciences
    GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre
    GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine
    University of Chinese Academy of Sciences)

  • Dominique Ferrandon

    (Guangzhou Medical University
    Université de Strasbourg
    UPR 9022 du CNRS)

  • Jing Liu

    (Chinese Academy of Sciences
    GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre
    GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine
    Guangzhou Medical University)

  • Duanqing Pei

    (Westlake University)

  • Jie Wang

    (Chinese Academy of Sciences
    GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre
    GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine
    Guangzhou Medical University)

  • Tao Wang

    (Chinese Academy of Sciences
    GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre
    GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine
    University of Chinese Academy of Sciences)

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.

Suggested Citation

  • 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 & , 2024. "Perturbation of METTL1-mediated tRNA N7- methylguanosine modification induces senescence and aging," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49796-8
    DOI: 10.1038/s41467-024-49796-8
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