The Functions of Fiona/Mett10/Mettl16 Family of m6A Methyltransferases

Chemical modifications of RNA bases play essential roles in finetuning the functions of the modified RNA species. The m(6)A modification is one of the most prevalent RNA modifications in nature with important functions in RNA stability, pre-mRNA splicing, translational regulations and likely others. m(6)A modifications in eukaryotes are believed to be mainly carried out by two related methyltransferases, METTL3 and METTL16 based on mammalian nomenclature. METTL16, similar to METTL3, has a large variety of RNA substrates, including pre-mRNA, rRNA, snRNA and lncRNA. Therefore, a unifying molecular function seems farfetched for the METTL16-installed m(6)A modification. In addition, METTL16 carries out important function in translational regulation independent of its methyltransferase activity, adding another layer of functional complexity to this highly conserved enzyme. In this review, we summarize the domain architecture of METTL16 and homologous proteins, indicating the conserved functional domains as well as the mammalian specific VCR domain suggestive of additional function of the higher enzymes. We summarize the confirmed METTL16-methylated RNA substrates as the pre-mRNA for SAM synthetase (MAT) in men and worms, and the U6 small nuclear RNA (snRNA) in yeast, plants, worms and men. Although the role of m(6)A modification in regulating SAM levels by alternative splicing might represent a case of convergent evolution, this proposition lacks support from plant studies of METTL16. The lack of m(6)A modification on U6 snRNA, an essential component of the spliceosome, has been identified in genome-wide studies as the cause for the splicing defects of specific introns in yeast and plants. How much of this function of U6 modification is conserved remains unclear. Mammalian METTL16 has been shown to carry out methylation-independent function by interacting with the machinery for protein synthesis. In addition, METTL16 was originally identified as the interacting protein of the triple-helix forming MALAT1, a long non-coding RNA highly expressed in certain tumors. However, whether MALAT1 is a methylation substrate of METTL16 and what underlies the biological significance of the METTL16-MALAT1 interaction remain under characterized. While knock-out mutants of METTL3 proteins suffer mild organismal consequences, those of METTL16 cause much more severe physiological abnormalities. How the conserved METTL16 enzymes fulfill an array of diverse and essential functions promises to be one of the fascinating directions in RNA biology.