Ghost authors revealed: The structure and function of human <scp><i>N</i>⁶</scp>‐methyladenosine <scp>RNA</scp> methyltransferases

Abstract

Abstract Despite the discovery of modified nucleic acids nearly 75 years ago, their biological functions are still being elucidated. N 6 ‐methyladenosine (m 6 A) 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, m 6 A 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 m 6 A marks in human RNAs have been known to exist since 1974, the structures and functions of methyltransferases responsible for writing m 6 A 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 N 6 position of adenosine, producing m 6 A: 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 m 6 A 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 m 6 A RNA methyltransferases, we present the biological functions and links to human disease, RNA targets, catalytic and kinetic mechanisms, and macromolecular structures. We also discuss m 6 A marks in human viruses and parasites, assigning m 6 A marks in the transcriptome to specific methyltransferases, small molecules targeting m 6 A methyltransferases, and the enzymes responsible for hypermodified m 6 A marks and their biological functions in humans. Understanding m 6 A methyltransferases is a critical steppingstone toward establishing the m 6 A epitranscriptome and more broadly the RNome. This article is categorized under: RNA Interactions with Proteins and Other Molecules &gt; Protein‐RNA Recognition RNA Interactions with Proteins and Other Molecules &gt; RNA‐Protein Complexes RNA Interactions with Proteins and Other Molecules &gt; Protein‐RNA Interactions: Functional Implications

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