Abstract |
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. |