The N6-methyladenosine (m6A) methyltransferase METTL3 promotes translation of oncogenes and is tethered to respective promoters. The mechanism by which m6A modification of mRNA through METTL3 promotes translation of target mRNAs has been identified in a recent paper published in Nature. Choe, Lin et al. show that METTL3 can only promote translation if bound to the 3′ untranslated region near the stop codon of the target mRNA. METTL3 interacts with the eukaryotic translation initiation factor 3 subunit h (eIF3h) in close proximity to the cap-binding protein, thereby promoting mRNA looping. eIF3h was needed for METTL3-mediated enhanced translation of a wide range of genes involved in tumour progression and apoptosis, including bromodomain-containing protein 4 (BRD4). METTL3 overexpression promoted invasion of mouse embryonic fibroblasts in vitro and tumour growth in vivo, for which interaction with eIF3h was required. Whether this interaction is targetable remains to be shown.
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Choe, J., Lin, S. et al. mRNA circularization by METTL3–eIF3h enhances translation and promotes oncogenesis. Nature 561, 556–560 (2018)
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Harjes, U. Oncogenic mRNA modification explained. Nat Rev Cancer 18, 667 (2018). https://doi.org/10.1038/s41568-018-0068-6
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DOI: https://doi.org/10.1038/s41568-018-0068-6