Non-AUG translation: a new start for protein synthesis in eukaryotes

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Abstract

This review by Kearse and Wilusz discusses the profound impact of non-AUG start codons in eukaryotic translation. It describes how misregulation of non-AUG initiation events contributes to multiple human diseases, including cancer and neurodegeneration, and how modulation of non-AUG usage may represent a novel therapeutic strategy.

Abstract

Although it was long thought that eukaryotic translation almost always initiates at an AUG start codon, recent advancements in ribosome footprint mapping have revealed that non-AUG start codons are used at an astonishing frequency. These non-AUG initiation events are not simply errors but instead are used to generate or regulate proteins with key cellular functions; for example, during development or stress. Misregulation of non-AUG initiation events contributes to multiple human diseases, including cancer and neurodegeneration, and modulation of non-AUG usage may represent a novel therapeutic strategy. It is thus becoming increasingly clear that start codon selection is regulated by many trans-acting initiation factors as well as sequence/structural elements within messenger RNAs and that non-AUG translation has a profound impact on cellular states.

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Most cited references 189

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N(6)-methyladenosine Modulates Messenger RNA Translation Efficiency.

Xiao Wang, Boxuan Simen Zhao, Ian A Roundtree … (2015)

N(6)-methyladenosine (m(6)A) is the most abundant internal modification in mammalian mRNA. This modification is reversible and non-stoichiometric and adds another layer to the dynamic control of mRNA metabolism. The stability of m(6)A-modified mRNA is regulated by an m(6)A reader protein, human YTHDF2, which recognizes m(6)A and reduces the stability of target transcripts. Looking at additional functional roles for the modification, we find that another m(6)A reader protein, human YTHDF1, actively promotes protein synthesis by interacting with translation machinery. In a unified mechanism of m(6)A-based regulation in the cytoplasm, YTHDF2-mediated degradation controls the lifetime of target transcripts, whereas YTHDF1-mediated translation promotion increases translation efficiency, ensuring effective protein production from dynamic transcripts that are marked by m(6)A. Therefore, the m(6)A modification in mRNA endows gene expression with fast responses and controllable protein production through these mechanisms.

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The integrated stress response.

Karolina Pakos-Zebrucka, Izabela Koryga, Katarzyna Mnich … (2016)

In response to diverse stress stimuli, eukaryotic cells activate a common adaptive pathway, termed the integrated stress response (ISR), to restore cellular homeostasis. The core event in this pathway is the phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α) by one of four members of the eIF2α kinase family, which leads to a decrease in global protein synthesis and the induction of selected genes, including the transcription factor ATF4, that together promote cellular recovery. The gene expression program activated by the ISR optimizes the cellular response to stress and is dependent on the cellular context, as well as on the nature and intensity of the stress stimuli. Although the ISR is primarily a pro-survival, homeostatic program, exposure to severe stress can drive signaling toward cell death. Here, we review current understanding of the ISR signaling and how it regulates cell fate under diverse types of stress.

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Genome-wide analysis in vivo of translation with nucleotide resolution using ribosome profiling.

Nicholas Ingolia, Sina Ghaemmaghami, John R S Newman … (2009)

Techniques for systematically monitoring protein translation have lagged far behind methods for measuring messenger RNA (mRNA) levels. Here, we present a ribosome-profiling strategy that is based on the deep sequencing of ribosome-protected mRNA fragments and enables genome-wide investigation of translation with subcodon resolution. We used this technique to monitor translation in budding yeast under both rich and starvation conditions. These studies defined the protein sequences being translated and found extensive translational control in both determining absolute protein abundance and responding to environmental stress. We also observed distinct phases during translation that involve a large decrease in ribosome density going from early to late peptide elongation as well as widespread regulated initiation at non-adenine-uracil-guanine (AUG) codons. Ribosome profiling is readily adaptable to other organisms, making high-precision investigation of protein translation experimentally accessible.

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Author and article information

Journal

Journal ID (nlm-ta): Genes Dev

Journal ID (iso-abbrev): Genes Dev

Journal ID (hwp): genesdev

Journal ID (pmc): genesdev

Journal ID (publisher-id): GAD

Title: Genes & Development

Publisher: Cold Spring Harbor Laboratory Press

ISSN (Print): 0890-9369

ISSN (Electronic): 1549-5477

Publication date (Print): 1 September 2017

Volume: 31

Issue: 17

Pages: 1717-1731

Affiliations

Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, 19104 USA

Author notes

Corresponding author: wilusz@ 123456pennmedicine.upenn.edu

Article

Medline ID: 8711660

DOI: 10.1101/gad.305250.117

PMC ID: 5666671

PubMed ID: 28982758

SO-VID: 6c9351d2-5e39-41d0-99e4-cb145adc0896

License:

This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

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Pages: 15

Funding

Funded by: National Institutes of Health , open-funder-registry 10.13039/100000002;

Award ID: R00-GM104166

Award ID: R35-GM119735

Funded by: National Cancer Institute , open-funder-registry 10.13039/100000054;

Award ID: NCI-P30-CA016520

Funded by: National Institutes of Health , open-funder-registry 10.13039/100000002;

Non-AUG translation: a new start for protein synthesis in eukaryotes

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Most cited references 189

N(6)-methyladenosine Modulates Messenger RNA Translation Efficiency.

The integrated stress response.

Genome-wide analysis in vivo of translation with nucleotide resolution using ribosome profiling.

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