mRNA circularization by METTL3-eIF3h enhances translation and promotes oncogenesis
By Junho Choe, Shuibin Lin, Wencai Zhang, Qi Liu, Longfei Wang, Julia Ramírez-Moya, P. Du, Wantae Kim, Shaojun Tang, P. Śliż and 7 more. Nature, 2018
646 citations recorded by the source corpus.
N6-methyladenosine (m6A) modification of mRNA is emerging as an important regulator of gene expression that affects different developmental and biological processes, and altered m6A homeostasis is linked to cancer1–5. m6A modification is catalysed by METTL3 and enriched in the 3′ untranslated region of a large subset of mRNAs at sites close to the stop codon5. METTL3 can promote translation but the mechanism and relevance of this process remain unknown1. Here we show that METTL3 enhances translation only when tethered to reporter mRNA at sites close to the stop codon, supporting a mechanism of mRNA looping for ribosome recycling and translational control. Electron microscopy reveals the topology of individual polyribosomes with single METTL3 foci in close proximity to 5′ cap-binding proteins. We identify a direct physical and functional interaction between METTL3 and the eukaryotic translation initiation factor 3 subunit h (eIF3h). METTL3 promotes translation of a large subset of oncogenic mRNAs—including bromodomain-containing protein 4—that is also m6A-modified in human primary lung tumours. The METTL3–eIF3h interaction is required for enhanced translation, formation of densely packed polyribosomes and oncogenic transformation. METTL3 depletion inhibits tumorigenicity and sensitizes lung cancer cells to BRD4 inhibition. These findings uncover a mechanism of translation control that is based on mRNA looping and identify METTL3–eIF3h as a potential therapeutic target for patients with cancer. METTL3, the enzyme responsible for m6A modification, influences translation by interacting with eIF3h to mediate looping between the regions near the stop codon and 5′ cap of mRNA.
Subfields: Cancer Research, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/027e8e814ca6854cdfd00e97cbcb35ab489c161d
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Citations in the corpus
- A Unified Model for the Function of YTHDF Proteins in Regulating m6A-Modified mRNA (2020, background): “, 2015), or m6A may be associated with bound METTL3, which may facilitate translation (Choe et al., 2018).”
- Functions of N6-methyladenosine and its role in cancer (2019, background): “METTL3 depletion leads to increased cell apoptosis and decreased cell growth and invasion, impairing tumorigenicity in mouse xenografts [43, 44].”
- Where, when and how: context-dependent functions of RNA methylation writers, readers, and erasers (2019, background): “Further studies showed that this translation promotion effect depends on interaction between METTL3 and eIF3h, which are coordinately overexpressed in many types of cancers (Choe et al., 2018).”
- m6A RNA methylation: from mechanisms to therapeutic potential (2021, neutral): “…of transcripts to promote cap-independent translation initiation, METTL3-mediated mRNA circularization to promote translation initiation, and the promotion of translation elongation by YTHDC2-mediated disruption of RNA secondary structures (Meyer et al , 2015; Choe et al , 2018; Mao et al , 2019).”