RNA (C5-cytosine) methyltransferases (RCMTs) catalyse the transfer of a methyl group to the 5th carbon of a cytosine base in RNA sequences to produce C5-methylcytosine. RCMTs use the cofactor S-adenosyl-L-methionine (SAM) as a methyl donor [1]. The catalytic mechanism of RCMTs involves an attack by the thiolate of a Cys residue on position 6 of the target cytosine base to form a covalent link, thereby activating C5 for methyl-group transfer. Following the addition of the methyl group, a second Cys residue acts as a general base in the beta-elimination of the proton from the methylated cytosine ring. The free enzyme is restored and the methylated product is released [2].

Numerous putative RCMTs have been identified in archaea, bacteria and eukaryota [3, 4]; most are predicted to be nuclear or nucleolar proteins [5]. The Escherichia coli Ribosomal RNA Small-subunit Methyltransferase Beta (RSMB) FMU (FirMicUtes) represents the first protein identified and characterised as a cytosine-specific RNA methyltransferase. RSMB was reported to catalyse the formation of C5-methylcytosine at position 967 of 16S rRNA [6, 7].

A classification of RCMTs has been proposed on the basis of sequence similarity [8]. According to this classification, RCMTs are divided into 8 distinct subfamilies [8]. Recently, a new RCMT subfamily, termed RCMT9, was identified [8]. Members of the RCMT contain a core domain, responsible for the cytosine-specific RNA methyltransferase activity. This 'catalytic' domain adopts the Rossmann fold for the accommodation of the cofactor SAM [8]. The RCMT subfamilies are also distinguished by N-terminal and C-terminal extensions, variable both in size and sequence [9].

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2. RNA methyltransferases utilize two cysteine residues in the formation of 5-methylcytosine. Biochemistry 41, 11218-25
3. Exposition of a family of RNA m(5)C methyltransferases from searching genomic and proteomic sequences. Nucleic Acids Res. 27, 3138-45
4. Phylogenetic analysis of the eukaryotic RNA (cytosine-5)-methyltransferases. Genomics 93, 350-7
5. 5-methylcytosine in RNA: detection, enzymatic formation and biological functions. Nucleic Acids Res. 38, 1415-30
6. Identification of the 16S rRNA m5C967 methyltransferase from Escherichia coli. Biochemistry 38, 4053-7
7. Purification, cloning, and characterization of the 16S RNA m5C967 methyltransferase from Escherichia coli. Biochemistry 38, 1884-92
8. Sequence-structure-function studies of tRNA:m5C methyltransferase Trm4p and its relationship to DNA:m5C and RNA:m5U methyltransferases. Nucleic Acids Res. 32, 2453-63

RNA (C5-cytosine) methyltransferases (RCMTs) catalyse the transfer of a methyl group to the 5th c
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