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 N6-methyladenosine (m6A) 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 m6A in 18S rRNA at position A1832 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 m6A in rRNA in stemness, differentiation, development, and diseases.

中文翻译：

---

rRNA m6A 甲基转移酶 METTL5 参与多能性和发育程序。

细胞 RNA 的共价化学修饰直接影响所有生物过程。然而，我们对催化这些修饰的酶、它们的底物和生物学功能的机制理解仍然含糊不清。在 RNA 修饰中，N6-甲基腺苷 (m6A) 广泛存在并存在于信使 (mRNA)、核糖体 (rRNA) 和非编码 RNA 中。在这里，我们进行了系统筛选以发现新的 RNA 甲基转移酶。我们证明甲基转移酶样 5 (METTL5) 蛋白在 A1832 位点催化 18S rRNA 中的 m6A 我们报告说，小鼠胚胎干细胞 (mESCs) 中 Mettl5 的缺失导致全局翻译率降低、多能性自发丧失和受损分化潜能。METTL5 缺陷小鼠以非孟德尔比率出生并出现形态和行为异常。重要的是，缺乏 METTL5 的小鼠重现了 METTL5 中 DNA 变异患者的症状，从而提供了一种新的小鼠疾病模型。总的来说，我们的生化、分子和体内表征突出了 rRNA 中 m6A 在干性、分化、发育和疾病中的重要性。