A comprehensive review of m(6)A/m(6)Am RNA methyltransferase structures

Gene expression is regulated at many levels including co- or post-transcriptionally, where chemical modifications are added to RNA on riboses and bases. Expression control via RNA modifications has been termed ‘epitranscriptomics’ to keep with the related ‘epigenomics’ for DNA modification. One such RNA modification is the N6-methylation found on adenosine (m(6)A) and 2′-O-methyladenosine (m(6)Am) in most types of RNA. The N6-methylation can affect the fold, stability, degradation and cellular interaction(s) of the modified RNA, implicating it in processes such as splicing, translation, export and decay. The multiple roles played by this modification explains why m(6)A misregulation is connected to multiple human cancers. The m(6)A/m(6)Am writer enzymes are RNA methyltransferases (MTases). Structures are available for functionally characterized m(6)A RNA MTases from human (m(6)A mRNA, m(6)A snRNA, m(6)A rRNA and m(6)Am mRNA MTases), zebrafish (m(6)Am mRNA MTase) and bacteria (m(6)A rRNA MTase). For each of these MTases, we describe their overall domain organization, the active site architecture and the substrate binding. We identify areas that remain to be investigated, propose yet unexplored routes for structural characterization of MTase:substrate complexes, and highlight common structural elements that should be described for future m(6)A/m(6)Am RNA MTase structures.