The METTL2-DALRD3 complex presents yet another case of a multi-subunit enzyme catalyzing tRNA modification. The emerging number of multimeric tRNA modification enzymes has been hypothesized to be driven by the need to recognize and modify different substrates while maintaining high specificity55,56. In one pertinent example, the activity of S. cerevisiae Trm140p on seryl-tRNA substrates is greatly stimulated by interaction with seryl-tRNA synthetase, which can recognize the full cellular repertoire of seryl-tRNAs even though their anticodons do not have any nucleotides in common25. Human METTL6 also interacts with seryl-tRNA synthetase32, providing further evidence that Trm140p homologs have evolved to bind additional protein cofactors in order to efficiently recognize their substrates. The interaction between human METTL2A/B and DALRD3 is analogous to the interaction of S. cerevisiae Trm140p with seryl-tRNA synthetase in that a tRNA methyltransferase interacts with a known or predicted tRNA-binding protein in order to catalyze tRNA modification. However, unlike the interaction of seryl-tRNA synthetase with Trm140p, which allows Trm140p to recognize and modify different seryl-tRNA isoacceptors in S. cerevisiae, the tRNA-binding specificity of DALRD3 limits METTL2A/B activity to only tRNA-Arg-UCU
