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

Kearse, Michael G.; Wilusz, Jeremy E.

doi:10.1101/gad.305250.117

Cited by 338 publications

(360 citation statements)

References 189 publications

(262 reference statements)

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“…Consistent with this, we and others observed that exogenous stressors or eIF2a phosphorylation selectively enhances RAN translation at both CGG repeats and GGGGCC repeats associated with ALS [30,32,39] in a near-AUG codon-dependent manner. Several other eIFs are known to modulate start codon fidelity [33,81]. eIF1 maintains the fidelity of scanning 43S PICs for AUG start codons by antagonizing the structural reconfigurations that follow AUG recognition [58,[60][61][62][63].…”

Section: Bel/ddx3x Selectively Modulates Fmr1 Ran Translation In Humamentioning

confidence: 99%

“…A key feature that distinguishes RAN translation from canonical translation is its use of non-AUG codons for initiation [10,[30][31][32]. The specificity for AUG start codons is simultaneously (and paradoxically) central to the integrity of eukaryotic and prokaryotic proteomes and an essential point of regulation for determining which, when, and how much protein is synthesized from a given mRNA transcript [81,[99][100][101][102]. RNA secondary structure-forming elements (including GC-rich NREs) are predicted to slow or stall Data information: For all panels, ****P ≤ 0.0001 for the specified statistical test (compiled from ≥ 3 replicates).…”

Section: A the Expression Of Plasmid-based Nl-3xf Reporters In Hek293mentioning

confidence: 99%

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DDX 3X and specific initiation factors modulate FMR 1 repeat‐associated non‐AUG‐initiated translation

Linsalata

Malik

et al. 2019

EMBO Reports

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A CGG trinucleotide repeat expansion in the 5′ UTR of FMR1 causes the neurodegenerative disorder Fragile X‐associated tremor/ataxia syndrome (FXTAS). This repeat supports a non‐canonical mode of protein synthesis known as repeat‐associated, non‐AUG (RAN) translation. The mechanism underlying RAN translation at CGG repeats remains unclear. To identify modifiers of RAN translation and potential therapeutic targets, we performed a candidate‐based screen of eukaryotic initiation factors and RNA helicases in cell‐based assays and a Drosophila melanogaster model of FXTAS. We identified multiple modifiers of toxicity and RAN translation from an expanded CGG repeat in the context of the FMR1 5′UTR. These include the DEAD‐box RNA helicase belle/DDX3X, the helicase accessory factors EIF4B/4H, and the start codon selectivity factors EIF1 and EIF5. Disrupting belle/DDX3X selectively inhibited FMR1 RAN translation in Drosophila in vivo and cultured human cells, and mitigated repeat‐induced toxicity in Drosophila and primary rodent neurons. These findings implicate RNA secondary structure and start codon fidelity as critical elements mediating FMR1 RAN translation and identify potential targets for treating repeat‐associated neurodegeneration.

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Section: Bel/ddx3x Selectively Modulates Fmr1 Ran Translation In Humamentioning

confidence: 99%

Section: A the Expression Of Plasmid-based Nl-3xf Reporters In Hek293mentioning

confidence: 99%

DDX 3X and specific initiation factors modulate FMR 1 repeat‐associated non‐AUG‐initiated translation

Linsalata

Malik

et al. 2019

EMBO Reports

View full text Add to dashboard Cite

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“…Leaky scanning also occurs on non‐uORF containing mRNAs and can act as a mechanism for alternative start codon selection, whereby a portion of ribosomes initiate at a downstream, in‐frame start codon. Most ORFs initiate with AUG start codons, although there is increasing evidence of initiation at other start codons, albeit often at a reduced frequency (Kearse & Wilusz, ). Several N ‐terminally extended proteins have been observed by ribosome footprinting following oxidative stress (Gerashchenko et al, ).…”

Section: Mrna‐specific Regulation: Roles Of Mrna Elementsmentioning

confidence: 99%

Translational regulation in response to stress in Saccharomyces cerevisiae

Crawford

Pavitt

2018

Yeast

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The budding yeast Saccharomyces cerevisiae must dynamically alter the composition of its proteome in order to respond to diverse stresses. The reprogramming of gene expression during stress typically involves initial global repression of protein synthesis, accompanied by the activation of stress-responsive mRNAs through both translational and transcriptional responses. The ability of specific mRNAs to counter the global translational repression is therefore crucial to the overall response to stress. Here we summarize the major repressive mechanisms and discuss mechanisms of translational activation in response to different stresses in S. cerevisiae. Taken together, a wide range of studies indicate that multiple elements act in concert to bring about appropriate translational responses. These include regulatory elements within mRNAs, altered mRNA interactions with RNA-binding proteins and the specialization of ribosomes that each contribute towards regulating protein expression to suit the changing environmental conditions.

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“…Recent ribosome footprinting experiments have revealed that thousands of non‐AUG codons are used as start codons for translation initiation genome‐wide . Selection of the appropriate start codon for initiation is a regulated process, involving eIF1, eIF1A, eIF2, eIF3, and eIF5 . Alterations in levels, stoichiometry, or activity of these factors can alter start codon selection.…”

Section: How Cellular Stress Affects Translationmentioning

confidence: 99%

Translation acrobatics: how cancer cells exploit alternate modes of translational initiation

2018

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Recent work has brought to light many different mechanisms of translation initiation that function in cells in parallel to canonical cap-dependent initiation. This has important implications for cancer. Canonical cap-dependent translation initiation is inhibited by many stresses such as hypoxia, nutrient limitation, proteotoxic stress, or genotoxic stress. Since cancer cells are often exposed to these stresses, they rely on alternate modes of translation initiation for protein synthesis and cell growth. Cancer mutations are now being identified in components of the translation machinery and in -regulatory elements of mRNAs, which both control translation of cancer-relevant genes. In this review, we provide an overview on the various modes of non-canonical translation initiation, such as leaky scanning, translation re-initiation, ribosome shunting, IRES-dependent translation, and mA-dependent translation, and then discuss the influence of stress on these different modes of translation. Finally, we present examples of how these modes of translation are dysregulated in cancer cells, allowing them to grow, to proliferate, and to survive, thereby highlighting the importance of translational control in cancer.

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

Cited by 338 publications

References 189 publications

DDX 3X and specific initiation factors modulate FMR 1 repeat‐associated non‐AUG‐initiated translation

DDX 3X and specific initiation factors modulate FMR 1 repeat‐associated non‐AUG‐initiated translation

Translational regulation in response to stress in Saccharomyces cerevisiae

Translation acrobatics: how cancer cells exploit alternate modes of translational initiation

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