Rajiv Kumar Bedi

1 Introduction Messenger RNA (mRNA) undergoes diverse chemical modifications that modulate its function and fate. Among these, N6-methyladenosine (m6A)—methylation at the nitrogen-6 position of adenosine within the consensus DRACH motif (D = A, G, or U; R = A or G; H = A, C, or U)—is the most abundant internal modification in eukaryotic mRNA [1].

eLife assessment This important study combines experimental and computational data to address crucial aspects of RNA methylation by a vital RNA methyltransferase (MTase). The authors have provided compelling, strong evidence, utilizing well-established techniques, to elucidate aspects of the methyl transfer mechanism of methyltransferase-like protein 3 (METTL3), which is a part of the METTL3-14 complex. This work will be of broad interest to biochemists, biophysicists, and cell biologists alike.

Abstract The complex of methyltransferase-like proteins 3 and 14 (METTL3-14) is the major enzyme that deposits N6-methyladenosine (m6A) modifications on mRNA in humans. METTL3-14 plays key roles in various biological processes through its methyltransferase (MTase) activity. However, little is known about its substrate recognition and methyl transfer mechanism from its cofactor and methyl donor S-adenosylmethionine (SAM).