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

Jia Cui, Erdem Sendinc, Qi Liu, Sujin Kim, Jaden Y. Fang and Richard I. Gregory ()
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Jia Cui: Boston Children’s Hospital
Erdem Sendinc: Boston Children’s Hospital
Qi Liu: Boston Children’s Hospital
Sujin Kim: Boston Children’s Hospital
Jaden Y. Fang: Boston Children’s Hospital
Richard I. Gregory: Boston Children’s Hospital

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50161-y

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