METTL3 Promotes mRNA Translation to Drive Tumorigenesis

The mRNA modification N⁶-methyladenosine (m⁶A) is catalyzed by the METTL3 enzyme, and m⁶A is enriched in the 3′ untranslated region (3′UTR) of mRNAs near the stop codon. METTL3 has been shown to enhance translation, but the mechanism by which this occurs has not been determined. Choe, Lin, and colleagues found that METTL3 promoted translation only when bound to the 3′UTR near a stop codon. Mechanistically, METTL3 interacted with the eukaryotic translation initiation factor 3 subunit h (eIF3h) to promote translation of target mRNAs, suggesting an mRNA looping mechanism to facilitate ribosome recycling and translational control. Electron microscopy further supported this model, indicating that METTL3 bound to mRNA ribonucleoprotein complexes termed polyribosomes in close proximity to 5′ cap-binding proteins. METTL3 depletion reduced the translation efficiency of a large subset of mRNAs. These identified METTL3 targets tended to have longer 3′UTRs and, as expected, exhibited reduced protein expression. One of the target proteins depleted by eIF3h knockdown was BRD4, and METTL3 knockdown was sufficient to rescue BRD4 expression. Further, METTL3 depletion reduced expression of BRD4 in lung cancer cells, rendering them more sensitive to a BRD4 inhibitor. The METTL3–eIF3h interaction was required for enhanced mRNA translation. The METTL3 A155P mutation disrupted the eIF3h interaction, without altering its mRNA association, thereby blocking METTL3-mediated enhancement of mRNA translation. The METTL3–eIF3h interaction promoted translation by altering the polyribosome conformation, with wild-type METTL3 resulting in more densely packed polyribosomes than the A155P mutant. METTL3 was upregulated in primary human lung adenocarcinomas compared with adjacent normal tissue, and, in vivo, METTL3 depletion suppressed the growth of lung cancer xenografts. Conversely, ectopic expression of METTL3 promoted tumor growth in vivo. Collectively, these findings suggest that METTL3 promotes oncogenic translation by interacting with eIF3h, facilitating an mRNA looping to increase target protein expression and drive tumorigenesis.

Choe J, Lin S, Zhang W, Liu Q, Wang L, Ramirez-Moya J, et al. mRNA circularization by METTL3-eIF3h enhances translation and promotes oncogenesis. Nature 2018;561:556–60.

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