TY - JOUR
T1 - The rRNA m6A methyltransferase METTL5 is involved in pluripotency and developmental programs
AU - Ignatova, Valentina V.
AU - Stolz, Paul
AU - Kaiser, Steffen
AU - Gustafsson, Tobias H.
AU - Lastres, Palma Rico
AU - Sanz-Moreno, Adrián
AU - Cho, Yi Li
AU - Amarie, Oana V.
AU - Aguilar-Pimentel, Antonio
AU - Klein-Rodewald, Tanja
AU - Calzada-Wack, Julia
AU - Becker, Lore
AU - Marschall, Susan
AU - Kraiger, Markus
AU - Garrett, Lillian
AU - Seisenberger, Claudia
AU - Hölter, Sabine M.
AU - Borland, Kayla
AU - de Logt, Erik Van
AU - Jansen, Pascal W.T.C.
AU - Baltissen, Marijke P.
AU - Valenta, Magdalena
AU - Vermeulen, Michiel
AU - Wurst, Wolfgang
AU - Gailus-Durner, Valerie
AU - Fuchs, Helmut
AU - de Angelis, Martin Hrabe
AU - Rando, Oliver J.
AU - Kellner, Stefanie M.
AU - Bultmann, Sebastian
AU - Schneider, Robert
N1 - Publisher Copyright:
© 2020 Ignatova et al.
PY - 2020/5/1
Y1 - 2020/5/1
N2 - 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.
AB - 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.
KW - MA
KW - Methyltransferase
KW - Pluripotency
UR - http://www.scopus.com/inward/record.url?scp=85084961210&partnerID=8YFLogxK
U2 - 10.1101/gad.333369.119
DO - 10.1101/gad.333369.119
M3 - Article
C2 - 32217665
AN - SCOPUS:85084961210
SN - 0890-9369
VL - 34
SP - 715
EP - 729
JO - Genes and Development
JF - Genes and Development
IS - 9-10
ER -