Roles and dynamics of 3-methylcytidine in cellular RNAs

Modified nucleotides within cellular RNAs significantly influence their biogenesis, stability, and function. As reviewed here, 3-methylcytidine (m³C) has recently come to the fore through the identification of the methyltransferases responsible for installing m³C₃₂ in human tRNAs. Mechanistic details of how m³C₃₂ methyltransferases recognize their substrate tRNAs have been uncovered and the biogenetic and functional relevance of interconnections between m³C₃₂ and modified adenosines at position 37 highlighted. Functional insights into the role of m³C₃₂ modifications indicate that they influence tRNA structure and, consistently, lack of m³C₃₂ modifications impairs translation. Development of quantitative, transcriptome-wide m³C mapping approaches and the discovery of an m³C demethylase reveal m³C to be dynamic, raising the possibility that it contributes to fine-tuning gene expression in different conditions.