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mRNA circularization by METTL3-eIF3h enhances translation and promotes oncogenesis
- Source :
- Nature, Digital.CSIC. Repositorio Institucional del CSIC, instname
- Publication Year :
- 2018
- Publisher :
- Nature Publishing Group, 2018.
-
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.<br />S.L. was supported by a Damon Runyon-Sohn Pediatric Fellowship (DRSG-7–13) and a grant from Alex’s Lemonade Stand Foundation. R.I.G. was supported by grants from the US National Institute of General Medical Sciences (NIGMS) (R01GM086386) and National Cancer Institute (NCI) (R01CA211328).
- Subjects :
- 0301 basic medicine
Untranslated region
Lung Neoplasms
Carcinogenesis
JQ1
Eukaryotic Initiation Factor-3
translation
Mice, Nude
closed loop
Article
Mice
03 medical and health sciences
Eukaryotic translation
oncogene
Cell Line, Tumor
Polysome
Protein biosynthesis
Animals
Humans
Initiation factor
RNA, Messenger
Messenger RNA
Multidisciplinary
N6-methyladenosine
Chemistry
Translation (biology)
m6A
Methyltransferases
lung adenocarcinoma
Stop codon
3. Good health
Cell biology
eIF3h
030104 developmental biology
Cyclization
Polyribosomes
Protein Biosynthesis
METTL3
BRD4
Nucleic Acid Conformation
Female
polysome
Protein Binding
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Nature, Digital.CSIC. Repositorio Institucional del CSIC, instname
- Accession number :
- edsair.doi.dedup.....20a1ea76cd84193ab4441c57165cd419