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m3C32 tRNA modification controls serine codon-biased mRNA translation, cell cycle, and DNA-damage response

Author

Listed:
  • Jia Cui

    (Boston Children’s Hospital
    Harvard Medical School)

  • Erdem Sendinc

    (Boston Children’s Hospital
    Harvard Medical School)

  • Qi Liu

    (Boston Children’s Hospital
    Harvard Medical School
    Guangdong Academy of Agricultural Sciences
    Guangdong Key Laboratory of New Technology in Rice Breeding)

  • Sujin Kim

    (Boston Children’s Hospital
    Harvard Medical School)

  • Jaden Y. Fang

    (Boston Children’s Hospital
    Harvard Medical School)

  • Richard I. Gregory

    (Boston Children’s Hospital
    Harvard Medical School
    Harvard Medical School
    Harvard Initiative for RNA Medicine)

Abstract

The epitranscriptome includes a diversity of RNA modifications that influence gene expression. N3-methylcytidine (m3C) mainly occurs in the anticodon loop (position C32) of certain tRNAs yet its role is poorly understood. Here, using HAC-Seq, we report comprehensive METTL2A/2B-, METTL6-, and METTL2A/2B/6-dependent m3C profiles in human cells. METTL2A/2B modifies tRNA-arginine and tRNA-threonine members, whereas METTL6 modifies the tRNA-serine family. However, decreased m3C32 on tRNA-Ser-GCT isodecoders is only observed with combined METTL2A/2B/6 deletion. Ribo-Seq reveals altered translation of genes related to cell cycle and DNA repair pathways in METTL2A/2B/6-deficient cells, and these mRNAs are enriched in AGU codons that require tRNA-Ser-GCT for translation. These results, supported by reporter assays, help explain the observed altered cell cycle, slowed proliferation, and increased cisplatin sensitivity phenotypes of METTL2A/2B/6-deficient cells. Thus, we define METTL2A/2B/6-dependent methylomes and uncover a particular requirement of m3C32 tRNA modification for serine codon-biased mRNA translation of cell cycle, and DNA repair genes.

Suggested Citation

  • Jia Cui & Erdem Sendinc & Qi Liu & Sujin Kim & Jaden Y. Fang & Richard I. Gregory, 2024. "m3C32 tRNA modification controls serine codon-biased mRNA translation, cell cycle, and DNA-damage response," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50161-y
    DOI: 10.1038/s41467-024-50161-y
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