The human 18S rRNA m ⁶A methyltransferase METTL5 is stabilized by TRMT112

Abstract

N6-methyladenosine (m ⁶A) has recently been found abundantly on messenger RNA and shown to regulate most steps of mRNA metabolism. Several important m ⁶A methyltransferases have been described functionally and structurally, but the enzymes responsible for installing one m ⁶A residue on each subunit of human ribosomes at functionally important sites have eluded identification for over 30 years. Here, we identify METTL5 as the enzyme responsible for 18S rRNA m ⁶A modification and confirm ZCCHC4 as the 28S rRNA modification enzyme. We show that METTL5 must form a heterodimeric complex with TRMT112, a known methyltransferase activator, to gain metabolic stability in cells. We provide the first atomic resolution structure of METTL5–TRMT112, supporting that its RNA-binding mode differs distinctly from that of other m ⁶A RNA methyltransferases. On the basis of similarities with a DNA methyltransferase, we propose that METTL5–TRMT112 acts by extruding the adenosine to be modified from a double-stranded nucleic acid.