Ghost authors revealed: The structure and function of human N6‐methyladenosine RNAmethyltransferases

Despite the discovery of modified nucleic acids nearly 75 years ago, their biological functions are still being elucidated. N6‐methyladenosine (m6A) is the most abundant modification in eukaryotic messenger RNA (mRNA) and has also been detected in non‐coding RNAs, including long non‐coding RNA, ribosomal RNA, and small nuclear RNA. In general, m6A marks can alter RNA secondary structure and initiate unique RNA–protein interactions that can alter splicing, mRNA turnover, and translation, just to name a few. Although m6A marks in human RNAs have been known to exist since 1974, the structures and functions of methyltransferases responsible for writing m6A marks have been established only recently. Thus far, there are four confirmed human methyltransferases that catalyze the transfer of a methyl group from S‐adenosylmethionine (SAM) to the N6position of adenosine, producing m6A: methyltransferase‐like protein (METTL) 3/METTL14 complex, METTL16, METTL5, and zinc‐finger CCHC‐domain‐containing protein 4. Though the methyltransferases have unique RNA targets, all human m6A RNA methyltransferases contain a Rossmann fold with a conserved SAM‐binding pocket, suggesting that they utilize a similar catalytic mechanism for methyl transfer. For each of the human m6A RNA methyltransferases, we present the biological functions and links to human disease, RNA targets, catalytic and kinetic mechanisms, and macromolecular structures. We also discuss m6A marks in human viruses and parasites, assigning m6A marks in the transcriptome to specific methyltransferases, small molecules targeting m6A methyltransferases, and the enzymes responsible for hypermodified m6A marks and their biological functions in humans. Understanding m6A methyltransferases is a critical steppingstone toward establishing the m6A epitranscriptome and more broadly the RNome. This article is categorized under:RNA Interactions with Proteins and Other Molecules > Protein‐RNA RecognitionRNA Interactions with Proteins and Other Molecules > RNA‐Protein ComplexesRNA Interactions with Proteins and Other Molecules > Protein‐RNA Interactions: Functional Implications The human N6‐methyladenosine (m6A) epitranscriptome as written by methyltransferase‐like protein (METTL) 3/METTL14 and three methyltransferases which are no longer ghost authors: METTL16, METTL5, and zinc‐finger CCHC‐domain‐containing protein 4.