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      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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          Most cited references 25

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

          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.

            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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              Synonymous mutations frequently act as driver mutations in human cancers.

              Synonymous mutations change the sequence of a gene without directly altering the sequence of the encoded protein. Here, we present evidence that these "silent" mutations frequently contribute to human cancer. Selection on synonymous mutations in oncogenes is cancer-type specific, and although the functional consequences of cancer-associated synonymous mutations may be diverse, they recurrently alter exonic motifs that regulate splicing and are associated with changes in oncogene splicing in tumors. The p53 tumor suppressor (TP53) also has recurrent synonymous mutations, but, in contrast to those in oncogenes, these are adjacent to splice sites and inactivate them. We estimate that between one in two and one in five silent mutations in oncogenes have been selected, equating to ~6%- 8% of all selected single-nucleotide changes in these genes. In addition, our analyses suggest that dosage-sensitive oncogenes have selected mutations in their 3' UTRs. Copyright © 2014 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                arb@stowers.org
                Journal
                EMBO J
                EMBO J
                10.1002/(ISSN)1460-2075
                EMBJ
                embojnl
                The EMBO Journal
                John Wiley and Sons Inc. (Hoboken )
                0261-4189
                1460-2075
                03 August 2020
                01 September 2020
                03 August 2020
                : 39
                : 17 ( doiID: 10.1002/embj.v39.17 )
                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

                Article
                EMBJ2020104763
                10.15252/embj.2020104763
                7459409
                32744758
                © 2020 The Authors. Published under the terms of the CC BY 4.0 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.

                Page count
                Figures: 12, Tables: 0, Pages: 13, Words: 11091
                Product
                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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                Article
                Articles
                Custom metadata
                2.0
                01 September 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.8 mode:remove_FC converted:01.09.2020

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