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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 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.

SUBMITTER: Ignatova VV

PROVIDER: S-EPMC7197354 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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

Ignatova Valentina V VV Stolz Paul P Kaiser Steffen S Gustafsson Tobias H TH Lastres Palma Rico PR Sanz-Moreno Adrián A Cho Yi-Li YL Amarie Oana V OV Aguilar-Pimentel Antonio A Klein-Rodewald Tanja T Calzada-Wack Julia J Becker Lore L Marschall Susan S Kraiger Markus M Garrett Lillian L Seisenberger Claudia C Hölter Sabine M SM Borland Kayla K Van De Logt Erik E Jansen Pascal W T C PWTC Baltissen Marijke P MP Valenta Magdalena M Vermeulen Michiel M Wurst Wolfgang W Gailus-Durner Valerie V Fuchs Helmut H Hrabe de Angelis Martin M Rando Oliver J OJ Kellner Stefanie M SM Bultmann Sebastian S Schneider Robert R

Genes & development 20200326 9-10

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 methylt ...[more]

PMID: 32217665

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Project description:BackgroundRibosomal RNA N6-methyltransferase METTL5 was reported to catalyze m6A in 18S rRNA. We aimed to investigate the expression and prognostic features of METTL5 in gastric cancer (GC).MethodsIn this study, 168 GC patients and their corresponding adjacent tissues were collected. Immunohistochemical staining was used to detect the expression of METTL5 protein. Univariate and multivariate Cox analysis were used to dertermine the prognostic role of METTL5 protein in GC, and a nomogram was constructed to evaluate GC patients' prognosis based on METTL5 expression. Data from TCGA and GEO database were also used to validate the prognostic value of METTL5 in GC patients on mRNA level. We further performed GSEA enrichment analysis to explore the possible function and related pathways related to METTL5.ResultsMETTL5 protein in gastric cancer tissues (GCTs) was significantly decreased compared with adjacent normal tissues (ANTs) and adjacent intestinal metaplasia tissues (AIMTs) (P < 0.001, respectively). Meanwhile, METTL5 expression was negatively correlated with clinicopathologic stage. According to multivariate Cox proportional hazards model analysis, METTL5 protein expression was a good independent predictor of GC prognosis (p < 0.05). Patients with high METTL5 expression had better prognosis. The nomogram constructed based on METTL5 expression could predict the prognosis of GC patients well. GSEA analysis showed that genes of METTL5 low expression group were enriched in some oncogenic signaling pathways such as ERBB, MAPK, JAK-STAT, Wnt, and mTOR, as well as some immune pathways, including Fc-gamma R mediated phagocytosis, Fc-epsilon Ri, chemokine, T cell receptor and B cell receptor signaling pathway. While the high expression group of METTL5 was mainly related to oxidative phosphorylation, nucleotide excision repair and mismatch repair.ConclusionsMETTL5 protein was decreased in GCTs compared with AIMTs and ANTs, and it may be a potential prognostic biomarker in GC.

Dataset Information

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

Publications

The rRNA m<sup>6</sup>A methyltransferase METTL5 is involved in pluripotency and developmental programs.

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