Ghost authors revealed: The structure and function of human N⁶ -methyladenosine RNA methyltransferases

Despite the discovery of modified nucleic acids nearly 75 years ago, their biological functions are still being elucidated. N⁶ -methyladenosine (m⁶ 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, m⁶ 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 m⁶ A marks in human RNAs have been known to exist since 1974, the structures and functions of methyltransferases responsible for writing m⁶ 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 N⁶ position of adenosine, producing m⁶ 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 m⁶ 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 m⁶ 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 m⁶ A marks in human viruses and parasites, assigning m⁶ A marks in the transcriptome to specific methyltransferases, small molecules targeting m⁶ A methyltransferases, and the enzymes responsible for hypermodified m⁶ A marks and their biological functions in humans. Understanding m⁶ A methyltransferases is a critical steppingstone toward establishing the m⁶ A epitranscriptome and more broadly the RNome. This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein-RNA Recognition RNA Interactions with Proteins and Other Molecules > RNA-Protein Complexes RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications.