A researcher’s guide to the galaxy of IRESs

Terenin, Ilya M.; Smirnova, Victoria V.; Andreev, Dmitry E.; Dmitriev, Sergey E.; Shatsky, Ivan N.

doi:10.1007/s00018-016-2409-5

Cited by 63 publications

(73 citation statements)

References 256 publications

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“…Based on further site-directed mutagenesis, the authors concluded that these G4s were part of IRESes (Internal Ribosome Entry Site), structures that initiate protein synthesis by a non-canonical 5'-cap-independent manner. While the presence of bona fide IRESes in viral genomes is well characterized, whether cellular IRESes exist is a matter of debate 146 . Under oxidative stress, the 5'-UTR of NRF2 mRNA (encoding the transcription factor NRF2, which regulates expression of antioxidant and detoxification genes) stimulates its translation in a G4-dependent manner 147 .…”

Section: Proposed Functions Of Rna G-quadruplexesmentioning

confidence: 99%

RNA G-Quadruplexes in Biology: Principles and Molecular Mechanisms

Fay

Lyons

Ivanov

2017

Journal of Molecular Biology

361

306

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G-quadruplexes are extremely stable DNA or RNA secondary structures formed by sequences rich in guanine. These structures are implicated in many essential cellular processes and the number of biological functions attributed to them continues to grow. While DNA G-quadruplexes are well understood on structural and to some extent on functional levels, RNA G-quadruplexes and their functions have received less attention. The presence of bona fide RNA G-quadruplexes in cells has long been a matter of debate. The development of G-quadruplex-specific antibodies and ligands hinted on their presence in vivo but recent advances in RNA sequencing coupled with chemical footprinting suggested the opposite. In this review, we will critically discuss the biology of RNA G-quadruplexes focusing on the molecular mechanisms underlying their proposed functions.

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Section: Proposed Functions Of Rna G-quadruplexesmentioning

confidence: 99%

RNA G-Quadruplexes in Biology: Principles and Molecular Mechanisms

Fay

Lyons

Ivanov

2017

Journal of Molecular Biology

361

306

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“…Normal protein synthesis was measured by the expression of full-length FLuc, and SCR was measured by the expression of NLuc when a PTC was inserted at position R154X (UGA). Importantly, by expressing each luciferase from a separate mRNA, we avoid many of the pitfalls that can confound interpretation of bicistronic reporters for studying stop codon readthrough (Loughran, Howard, Firth, & Atkins, 2017;Terenin, Smirnova, Andreev, Dmitriev, & Shatsky, 2017).…”

Section: Aminoglycosides Promote Ptc Readthrough While Simultaneouslymentioning

confidence: 99%

Stop Codon Context Influences Genome-Wide Stimulation of Termination Codon Readthrough by Aminoglycosides

Wangen

Green

2019

Preprint

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Stop codon readthrough (SCR) occurs when the ribosome miscodes at a stop codon. Such readthrough events can be therapeutically desirable when a premature termination codon (PTC) is found in a critical gene. To study SCR in vivo in a genome-wide manner, we treated mammalian cells with aminoglycosides and performed ribosome profiling. We find that in addition to stimulating readthrough of PTCs, aminoglycosides stimulate readthrough of normal termination codons (NTCs) genome-wide. Stop codon identity, the nucleotide following the stop codon, and the surrounding mRNA sequence context all influence the likelihood of SCR. In comparison to NTCs, downstream stop codons in 3′UTRs are recognized less efficiently by ribosomes, suggesting that targeting of critical stop codons for readthrough may be achievable without general disruption of translation termination. Finally, we find that G418 treatment globally alters gene expression with substantial effects on translation of histone genes, selenoprotein genes, and S-adenosylmethionine decarboxylase (AMD1).

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“…Our findings are reminiscent of the manner in which viruses use highly structured IRESs to directly recruit eIFs, the 40S subunit, and/or the 43S PIC to drive the cap-independent translation of viral mRNA (5,42,43). Although the mechanisms through which viral mRNAs use IRESs to drive cap-independent initiation have been extensively characterized using genetic, biochemical, and structural approaches (16,44,45), the mechanisms through which eukaryotic cellular mRNAs drive cap-independent initiation remain largely unknown.…”

Section: Discussionmentioning

confidence: 86%

5’ UTR recruitment of eIF4GI or DAP5 drives cap-independent translation for a subset of human mRNAs

Sa¹,

Bhardwaj²,

Gonzalez³

et al. 2018

Preprint

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Running title: eIF4GI or DAP5 drives cap-independent translation initiationKeywords: 5' CITE | IRES | eIF4GI | DAP5 | fluorescence anisotropy AbstractDuring unfavorable human cellular conditions (e.g., tumor hypoxia, viral infection, etc.), canonical, cap-dependent mRNA translation is suppressed. Nonetheless, a subset of physiologically important mRNAs (e.g., HIF-1α, FGF-9, and p53) is still translated by an unknown, capindependent mechanism. Additionally, expression levels of eIF4G and its homolog, death associated protein 5 (DAP5), are elevated. Using fluorescence anisotropy binding studies, luciferase reporter-based in vitro translation assays, and mutational analyses, here we demonstrate that eIF4GI and DAP5 specifically bind to the 5' UTRs of these cap-independently translated mRNAs. Surprisingly, we find that the eIF4E binding domain of eIF4GI increases not only the binding affinity, but also the selectivity among these mRNAs. We further demonstrate that the affinities of eIF4GI and DAP5 binding to these 5' UTRs correlate with the efficiency with which these factors drive cap-independent translation of these mRNAs. Integrating the results of our binding and translation assays, we show that eIF4GI and/or DAP5 are critical for recruitment of a specific subset of mRNAs to the ribosome and provide mechanistic insight into their capindependent translation. Running title: eIF4GI or DAP5 drives cap-independent translation initiationKeywords: 5' CITE | IRES | eIF4GI | DAP5 | fluorescence anisotropy

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A researcher’s guide to the galaxy of IRESs

Cited by 63 publications

References 256 publications

RNA G-Quadruplexes in Biology: Principles and Molecular Mechanisms

RNA G-Quadruplexes in Biology: Principles and Molecular Mechanisms

Stop Codon Context Influences Genome-Wide Stimulation of Termination Codon Readthrough by Aminoglycosides

5’ UTR recruitment of eIF4GI or DAP5 drives cap-independent translation for a subset of human mRNAs

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