m 3 C32 tRNA modification controls serine codon-biased mRNA translation, cell cycle, and DNA-damage response.
Jia CuiErdem SendincQi LiuSujin KimJaden Y FangRichard I GregoryPublished in: Nature communications (2024)
The epitranscriptome includes a diversity of RNA modifications that influence gene expression. N3-methylcytidine (m 3 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 3 C profiles in human cells. METTL2A/2B modifies tRNA-arginine and tRNA-threonine members, whereas METTL6 modifies the tRNA-serine family. However, decreased m 3 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 3 C32 tRNA modification for serine codon-biased mRNA translation of cell cycle, and DNA repair genes.
Keyphrases
- cell cycle
- dna repair
- dna damage response
- cell proliferation
- dna damage
- gene expression
- genome wide
- induced apoptosis
- protein kinase
- dna methylation
- signaling pathway
- single cell
- cell cycle arrest
- rna seq
- high throughput
- crispr cas
- transcription factor
- drug induced
- cell death
- genome wide identification
- genome wide analysis