Figure 1.

Mechanisms of C5-methylation of cytosine by m⁵C RNA methyltransferases. (a) Amino acid sequence alignment of regions forming the active sites of human m⁵C methyltransferases. Top: NSUN family of m⁵C RNA methyltransferases, bottom DNMT family containing DNMT2 as RNA methyltransferase and DNMT1 and DNMT3A/B as DNA methyltransferases. The conserved motifs IV and VI are boxed. The catalytic cysteine that forms a covalent bond with C6 of the target cytosine is marked with magenta background, and is located in motif VI in NSUN methyltransferases, and in motif IV in DNMT methyltransferases. (b) The catalytic mechanism is depicted in detail for NSUN6 (see text for description). (c) The active site in the crystal structure of NSUN6 with target RNA is presented, showing the arrangement and key contacts between the amino acids in the active site and the target cytosine (C72) in RNA (PDB 5WWS).