Translation of small downstream ORFs enhances translation of canonical main open reading frames

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Abstract

Abstract In addition to canonical open reading frames (ORFs), thousands of translated small ORFs (containing less than 100 codons) have been identified in untranslated mRNA regions (UTRs) across eukaryotes. Small ORFs in 5′ UTRs (upstream (u)ORFs) often repress translation of the canonical ORF within the same mRNA. However, the function of translated small ORFs in the 3′ UTRs (downstream (d)ORFs) is unknown. Contrary to uORFs, we find that translation of dORFs enhances translation of their corresponding canonical ORFs. This translation stimulatory effect of dORFs depends on the number of dORFs, but not the length or peptide they encode. We propose that dORFs represent a new, strong, and universal translation regulatory mechanism in vertebrates.

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mRNA circularization by METTL3-eIF3h enhances translation and promotes oncogenesis

Junho Choe, Shuibin Lin, Wencai Zhang … (2018)

N 6-Methyladenosine (m6A) modification of messenger RNA (mRNA) is emerging as an important regulator of gene expression that impacts different developmental and biological processes, and altered m6A homeostasis is linked to cancer 1-5 . 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 codon 5 . METTL3 can promote translation but the mechanism and widespread relevance remain unknown 1 . 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 target.

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Ribosome profiling shows that miR-430 reduces translation before causing mRNA decay in zebrafish.

Ariel Bazzini, Miler T. Lee, Antonio Giraldez (2012)

MicroRNAs regulate gene expression through deadenylation, repression, and messenger RNA (mRNA) decay. However, the contribution of each mechanism in non-steady-state situations remains unclear. We monitored the impact of miR-430 on ribosome occupancy of endogenous mRNAs in wild-type and dicer mutant zebrafish embryos and found that miR-430 reduces the number of ribosomes on target mRNAs before causing mRNA decay. Translational repression occurs before complete deadenylation, and disrupting deadenylation with use of an internal polyadenylate tail did not block target repression. Lastly, we observed that ribosome density along the length of the message remains constant, suggesting that translational repression occurs by reducing the rate of initiation rather than affecting elongation or causing ribosomal drop-off. These results show that miR-430 regulates translation initiation before inducing mRNA decay during zebrafish development.

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Identification of small ORFs in vertebrates using ribosome footprinting and evolutionary conservation.

A. A. Bazzini, T. G. Johnstone, R. Christiano … (2014)

Identification of the coding elements in the genome is a fundamental step to understanding the building blocks of living systems. Short peptides (< 100 aa) have emerged as important regulators of development and physiology, but their identification has been limited by their size. We have leveraged the periodicity of ribosome movement on the mRNA to define actively translated ORFs by ribosome footprinting. This approach identifies several hundred translated small ORFs in zebrafish and human. Computational prediction of small ORFs from codon conservation patterns corroborates and extends these findings and identifies conserved sequences in zebrafish and human, suggesting functional peptide products (micropeptides). These results identify micropeptide-encoding genes in vertebrates, providing an entry point to define their function in vivo.