METTL3METTL14

METTL3-METTL14 is a heterodimeric RNA methyltransferase complex that installs N6-methyladenosine (m6A) marks on mRNA and other RNA species in eukaryotic cells. METTL3 is the primary catalytic subunit that binds S-adenosyl-L-methionine (SAM) and transfers the methyl group, while METTL14 acts as an essential regulatory partner that stabilizes the RNA-binding interface and enhances substrate recognition. The heterodimer forms the core of the m6A writer complex, frequently associating with cofactors such as WTAP, VIRMA (KIAA1429), ZC3H13, and RBM15/RBM15B, which influence nuclear localization, target specificity, and complex assembly.

METTL3 contains the catalytic DPPW motif; METTL14 lacks catalytic activity due to substitutions but structurally resembles METTL3's catalytic domain. The two subunits pair to form the active site, enabling transfer of a methyl group from SAM to adenosine within RNA, typically at DRACH sequence motifs (D = A/G/U, R = A/G, H = A/C/U).

Localization and function: The METTL3-METTL14 complex localizes to the nucleus and deposits m6A co-transcriptionally on nascent transcripts. m6A marks influence RNA metabolism, including splicing, export, stability, and translation, and contribute to development, differentiation, and stress responses. Reversible demethylation by ALKBH5 and FTO can remove m6A, allowing dynamic regulation of methylation status.

Discovery: The complex was characterized in the mid-2010s; METTL3 and METTL14 are evolutionarily conserved homologs, with METTL3 providing catalytic activity and METTL14 providing RNA-binding support. Structural and biochemical studies have detailed their interaction and dependence on cofactors for efficient methylation.