mRNA circularization by METTL3–eIF3h enhances translation and promotes oncogenesis
Jun-Ho Choe,Shuibin Lin,Shuibin Lin,Shuibin Lin,Wen Cai Zhang,Qi Liu,Qi Liu,Longfei Wang,Julia Ramírez-Moya,Julia Ramírez-Moya,Peng Du,Peng Du,Wantae Kim,Shaojun Tang,Piotr Sliz,Pilar Santisteban,Rani E. George,William G. Richards,Kwok-Kin Wong,Nicolas Locker,Frank J. Slack,Frank J. Slack,Richard I. Gregory +22 more
TLDR
It is shown 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.Abstract:
N6-Methyladenosine (m6A), the most abundant posttranscriptional messenger RNA (mRNA)
modification, is emerging as an important regulator of gene expression1 Manipulation of m6A
impacts different developmental and biological processes, and altered m6A homeostasis is
linked to cancer2-5 m6A is catalyzed by METTL3 and enriched in the 3’ untranslated region (3’
UTR) of a large subset of mRNAs at sites close to the stop codon1 METTL3 can promote
translation but the mechanism and widespread relevance remain unknown2 Here we show that
METTL3 enhances translation only when tethered to reporter mRNA at sites close to the stop
codon supporting a mRNA looping mechanism for ribosome recycling and translational
control Electron microscopy reveals the topology of individual polyribosomes with single
METTL3 foci found 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 (BRD4) that are also m6A-modified in human
primary lung tumors 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 mRNA looping mechanism of translation control and identify METTL3-eIF3h as a
potential cancer therapeutic targetread more
Citations
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Journal ArticleDOI
Reading, writing and erasing mRNA methylation.
TL;DR: New and emerging methods to characterize and quantify the epitranscriptome are reviewed, and new concepts — in some cases, controversies — are discussed regarding the authors' understanding of the mechanisms and functions of m6A readers, writers and erasers are discussed.
Journal ArticleDOI
Where, When, and How: Context-Dependent Functions of RNA Methylation Writers, Readers, and Erasers
TL;DR: This review highlights recent progress in understanding the function of N6-methyladenosine (m6A), the most abundant internal mark on eukaryotic mRNA, in light of the specific biological contexts of m6A effectors, and emphasizes the importance of context for RNA modification regulation and function.
Journal ArticleDOI
Functions of N6-methyladenosine and its role in cancer.
TL;DR: Al Alteration of m6A levels participates in cancer pathogenesis and development via regulating expression of tumor-related genes like BRD4, MYC, SOCS2 and EGFR and corresponding potential targets in cancer therapy are reviewed.
Journal ArticleDOI
m6A Modification in Coding and Non-coding RNAs: Roles and Therapeutic Implications in Cancer
TL;DR: The up-to-date knowledge of the pathological roles and underlying molecular mechanism of m6A modifications (in both coding and non-coding RNAs) in cancer pathogenesis and drug response/resistance are reviewed, and the therapeutic potential of targeting m 6A regulators for cancer therapy is discussed.
Journal ArticleDOI
The potential role of RNA N6-methyladenosine in Cancer progression
TL;DR: This review focuses on the physiological functions of m6A modification and its related regulators, as well as on the potential biological roles of these elements in human tumors.
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