%0 Journal Article
%T m3C32 tRNA modification controls serine codon-biased mRNA translation, cell cycle, and DNA-damage response.
%A Cui J
%A Sendinc E
%A Liu Q
%A Kim S
%A Fang JY
%A Gregory RI
%J Nat Commun
%V 15
%N 1
%D 2024 Jul 10
%M 38982125
%F 17.694
%R 10.1038/s41467-024-50161-y
%X 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.