The rRNA m⁶A methyltransferase METTL5 is involved in pluripotency and developmental programs

Abstract

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 6-methyladenosine (m 6 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 6 A in 18S rRNA at position A 1832. We report that absence of Mettl5 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 METTL5, thereby providing a new mouse disease model. Overall, our biochemical, molecular, and in vivo characterization highlights the importance of m 6 A in rRNA in stemness, differentiation, development, and diseases.

METTL5, an 18S rRNA-specific m6A methyltransferase, modulates expression of stress response genes

“…is also an American Cancer Society Research Professor; 3. During the preparation of this manuscript for publication, two other studies have been published that also documented the role of METTL5 as an 18S rRNA-specific methyltransferase (57,58). And in one of the studies METTL5 has also been shown to regulate stress-related genes in C. elegans (58), which suggests the involvement of METTL5 in stress response may be conserved during evolution.…”

The role of m6A modification in physiology and disease

“…METTL5 was defined as the methyltransferase of 18S rRNA, ZCCHC4 was defined as the methyltransferase of 28S rRNA, and TRMT112 acts as a methyltransferase activator to stabilize METTL5 in cells 37 . METTL5 was also reported to be involved in the pluripotency and differentiation potential of mouse embryonic stem cells and the fly behavior of Drosophila 38,39 .…”

Analysis of m6A RNA methylation in Caenorhabditis elegans

“…Note-added-in-proof: While this manuscript was under review, multiple studies showed that METTL5 mediates m6A methylation on the small subunit ribosomal RNA in flies, worms, mice, and human cells [13][14][15][16] . Collectively, our findings as well as the above referenced recent studies further support the conclusion that METTL5 is an evolutionarily conserved rRNA m6A methyltransferase.…”