The rRNA m6A methyltransferase METTL5 is involved in pluripotency and developmental programs
The rRNA m6A methyltransferase METTL5 is involved in pluripotency and developmental programs
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DOI：
10.1126/sciadv.aaz4551
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发表时间：
2020-05-01
影响因子：
10.5
通讯作者：
Schneider, Robert
中科院分区：
文献类型：
--
作者：
Ignatova, Valentina V.;Stolz, Paul;Schneider, Robert
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械理解仍然模糊。在RNA修饰中，N-6-甲基腺苷（m（6）A）广泛存在于信使（mRNA）、核糖体（rRNA）和非编码RNA中。在这里，我们进行了系统的筛选，以发现新的RNA甲基转移酶。我们证明，甲基转移酶样5（胃L5）蛋白催化18 S rRNA的位置A（1832）的m（6）A。我们报告说，Mett 15在小鼠胚胎干细胞（mESCs）的缺乏导致全球翻译率下降，自发丧失多能性，并损害分化潜力。胃L5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，缺乏胃L5的小鼠重现了具有胃L5中的DNA变体的患者的症状，从而提供了新的小鼠疾病模型。总的来说，我们的生物化学，分子和体内表征突出了m（6）A在干性，分化，发育和疾病中rRNA的重要性。
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 Mett15 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.