mRNA circularization by METTL3-eIF3h enhances translation and promotes oncogenesis

Area of Science:

• Molecular Biology
• Gene Expression Regulation
• Cancer Biology

Background:

• N⁶-methyladenosine (m⁶A) mRNA modification is a key regulator of gene expression implicated in cancer.
• METTL3 catalyzes m⁶A modification, particularly near the stop codon, and is known to influence translation, though the mechanism is unclear.

Purpose of the Study:

• To elucidate the mechanism by which METTL3 enhances mRNA translation.
• To investigate the functional relevance of METTL3 in cancer, specifically lung tumors.
• To identify potential therapeutic targets for cancer treatment based on METTL3 function.

Main Methods:

• Reporter mRNA assays to study METTL3's effect on translation when tethered.
• Electron microscopy to visualize polyribosome topology and protein interactions.
• Co-immunoprecipitation to identify physical interactions between METTL3 and translation factors.
• Analysis of m⁶A-modified oncogenic mRNAs in human lung tumors.

Main Results:

• METTL3 enhances translation via mRNA looping near the stop codon, involving interaction with 5' cap-binding proteins.
• A direct physical and functional interaction between METTL3 and eukaryotic translation initiation factor 3 subunit h (eIF3h) was identified.
• METTL3 promotes the translation of oncogenic mRNAs, including BRD4, in lung tumors, driving oncogenic transformation.
• METTL3 depletion inhibits tumor growth and increases sensitivity to BRD4 inhibitors.

Conclusions:

• METTL3 utilizes an mRNA looping mechanism to control translation, involving interaction with eIF3h.
• This METTL3-eIF3h pathway is crucial for oncogenic mRNA translation and transformation in lung cancer.
• The METTL3-eIF3h interaction represents a promising therapeutic target for cancer treatment.