rRNA N(6)-adenosine-methyltransferase METTL5
rRNA (adenine-N6-)-methyltransferase activity
The rRNA m<sup>6</sup>A methyltransferase METTL5 is involved in pluripotency and developmental programs.
Covalent chemical modifications of cellular RNAs directly impact all biological processes. However, our mechanistic understanding of the enzymes catalyzing these modifications, their substrates and biological functions, remains vague. Amongst RNA modifications N<sup>6</sup>-methyladenosine (m<sup>6</sup>A) is widespread and found in messenger (mRNA), ribosomal (rRNA), and noncoding RNAs. Here, we undertook a systematic screen to uncover new RNA methyltransferases. We demonstrate that the methyltransferase-like 5 (METTL5) protein catalyzes m<sup>6</sup>A in <i>18S</i> rRNA at position A<sub>1832</sub> We report that absence of <i>Mettl5</i> in mouse embryonic stem cells (mESCs) results in a decrease in global translation rate, spontaneous loss of pluripotency, and compromised differentiation potential. METTL5-deficient mice are born at non-Mendelian rates and develop morphological and behavioral abnormalities. Importantly, mice lacking METTL5 recapitulate symptoms of patients with DNA variants in <i>METTL5</i>, thereby providing a new mouse disease model. Overall, our biochemical, molecular, and in vivo characterization highlights the importance of m<sup>6</sup>A in rRNA in stemness, differentiation, development, and diseases.