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

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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.

Abstract

In contrast to upstream ORFs, translation of small open reading frames located in 3′ untranslated regions of mRNA promotes translation of the canonical ORF, independent of length or sequence of the encoded peptide.

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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.

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Author and article information

Contributors

Ariel A Bazzini:

ORCID: https://orcid.org/0000-0002-2251-5174

arb@stowers.org

Journal

Journal ID (nlm-ta): EMBO J

Journal ID (iso-abbrev): EMBO J

Journal ID (doi): 10.1002/(ISSN)1460-2075

Journal ID (publisher-id): EMBJ

Journal ID (hwp): embojnl

Title: The EMBO Journal

Publisher: John Wiley and Sons Inc. (Hoboken )

ISSN (Print): 0261-4189

ISSN (Electronic): 1460-2075

Publication date (Electronic): 03 August 2020

Publication date (Print): 01 September 2020

Publication date PMC-release: 03 August 2020

Volume: 39

Issue: 17 ( doiID: 10.1002/embj.v39.17 )

Electronic Location Identifier: e104763

Affiliations

[ ¹ ] Stowers Institute for Medical Research Kansas City MO USA

[ ² ] Department of Molecular and Integrative Physiology University of Kansas Medical Center Kansas City KS USA

Author notes

[*] [* ]Corresponding author. Tel: +1 816 926 4119; E‐mail: arb@ 123456stowers.org

[†]

These authors contributed equally to this work

Author information

Qiushuang Wu https://orcid.org/0000-0002-9301-3630

Matthew Wright https://orcid.org/0000-0002-6634-934X

Ariel A Bazzini https://orcid.org/0000-0002-2251-5174

Article

Publisher ID: EMBJ2020104763

DOI: 10.15252/embj.2020104763

PMC ID: 7459409

PubMed ID: 32744758

SO-VID: 61575eba-3bb2-4d39-99c4-e4a3837550ac

License:

This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

History

Date received : 19 February 2020

Date revision received : 23 June 2020

Date accepted : 26 June 2020

Page count

Figures: 12, Tables: 0, Pages: 13, Words: 11091

Funding

Funded by: Stowers Institute for Medical Research (SIMR) , open-funder-registry 10.13039/100007795;

Funded by: Pew Charitable Trusts , open-funder-registry 10.13039/100000875;

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source-schema-version-number 2.0

cover-date 01 September 2020

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.8 mode:remove_FC converted:01.09.2020

ScienceOpen disciplines: Molecular biology

Keywords: dorf,ribosome profiling,translation efficiency,chromatin, epigenetics, genomics & functional genomics,protein biosynthesis & quality control

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ScienceOpen disciplines: Molecular biology

Keywords: dorf, ribosome profiling, translation efficiency, chromatin, epigenetics, genomics & functional genomics, protein biosynthesis & quality control

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

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Abstract

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Higher order chromatin architecture

Most cited references 25

mRNA circularization by METTL3-eIF3h enhances translation and promotes oncogenesis

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

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

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