Four human homologs of Trm140p have been identified by sequence homology, which are encoded by the METTL2A, METTL2B, METTL6, and METTL8 genes17,31. METTL6 is responsible for the catalysis of m3C at position 32 in tRNA-Ser while METTL8 has been proposed to play a role in mRNA modification32. METTL2A and METTL2B encode paralogous proteins that share 99% amino acid sequence identity and form their own vertebrate-specific phylogenetic clade with METTL8 homologs within the Trm140p homology tree17,23,24. Like S. cerevisiae Trm140p and S. pombe Trm140p, METTL2A and 2B are required for the formation of m3C in threonyl-tRNAs32. In addition, human METTL2A and METTL2B are required for m3C formation in the arginine tRNA isoacceptors, tRNA-Arg-CCU and Arg-UCU. The presence of m3C in tRNA-Arg-CCU and Arg-UCU has been detected in multiple mammalian species but not in yeast or plants17,19,20,33,34, suggesting that METTL2A/B-catalyzed modification of arginine tRNAs evolved within the animal kingdom. However, the molecular mechanism by which METTL2A and 2B recognizes only a subset of arginine tRNA substrates as well as the biological roles of m3C modification in mammals are unknown.
