m<sup>3</sup>C32 tRNA modification controls serine codon-biased mRNA translation, cell cycle, and DNA-damage response.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 38982125.
- Also identified by DOI 10.1038/s41467-024-50161-y and PMC identifier 11233606.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
The epitranscriptome includes a diversity of RNA modifications that influence gene expression. N3-methylcytidine (m<sup>3</sup>C) 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 m<sup>3</sup>C profiles in human cells. METTL2A/2B modifies tRNA-arginine and tRNA-threonine members, whereas METTL6 modifies the tRNA-serine family. However, decreased m<sup>3</sup>C32 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 m<sup>3</sup>C32 tRNA modification for serine codon-biased mRNA translation of cell cycle, and DNA repair genes.
Medical subject headings
- Cell Cycle
- DNA Damage
- Protein Biosynthesis
- Codon
- RNA, Messenger
- RNA, Transfer
- Serine