N6‐methyladenosine modification in mRNA: machinery, function and implications for health and diseases

Abstract

N6-methyladenosine (m⁶A) modification in mRNA is extremely widespread, and functionally modulates the eukaryotic transcriptome to influence mRNA splicing, export, localization, translation, and stability. Methylated adenines are present in a large subset of mRNAs and long noncoding RNAs (lncRNAs). Methylation is reversible, and this is accomplished by the orchestrated action of highly conserved methyltransferase (m⁶A writer) and demethylase (m⁶A eraser) enzymes to shape the cellular ‘epitranscriptome’. The engraved ‘methyl code’ is subsequently decoded and executed by a group of m⁶A reader/effector components, which, in turn, govern the fate of the modified transcripts, thereby dictating their potential for translation. Reversible mRNA methylation thus adds another layer of regulation at the post-transcriptional level in the gene expression programme of eukaryotes that finely sculpts a highly dynamic proteome in order to respond to diverse cues during cellular differentiation, immune tolerance, and neuronal signalling