Systematic discovery of cap-independent translation sequences in human and viral genomes

Weingarten-Gabbay, Shira; Elias-Kirma, Shani; Nir, Ronit; Gritsenko, Alexey A.; Stern-Ginossar, Noam; Yakhini, Zohar; Weinberger, Adina; Segal, Eran

doi:10.1126/science.aad4939

Cited by 284 publications

(283 citation statements)

References 58 publications

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“…This was based on previous studies showing that DAP5 drives translation of its targets via IRES elements within the 5 ′ UTR (Henis- Korenblit et al 2002;Nevins et al 2003;Warnakulasuriyarachchi et al 2004;Lewis et al 2008;Marash et al 2008;Weingarten-Gabbay et al 2014). We used a previously described function-based screen in a cell-free system (Liberman et al 2015), since, despite some proposed in silico approaches (Baird et al 2006;Wu et al 2009;Weingarten-Gabbay et al 2016), it is difficult to a priori predict IRESs within a candidate mRNA. In this manner, HMGN3 was identified to have cap-independent translation ability, which was further confirmed in vivo in hESCs by showing that its 5 ′ UTR drives DAP5-dependent/cap-independent translation.…”

Section: Discussionmentioning

confidence: 99%

“…Considering previous reports showing that the 3 ′ UTR can also contribute to cap-independent translation (Izquierdo and Cuezva 2000;Martinez-Salas et al 2008;Bradley et al 2012;Bukhari et al 2016;Weingarten-Gabbay et al 2016), IRESs or elements that affect IRES activity may have been missed in this screen. Future screens can be conducted to include the 3 ′ UTR in the reporter plasmids and expand the number of targets assayed.…”

Section: Discussionmentioning

confidence: 99%

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Cap-independent translation by DAP5 controls cell fate decisions in human embryonic stem cells

et al. 2016

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Multiple transcriptional and epigenetic changes drive differentiation of embryonic stem cells (ESCs). This study unveils an additional level of gene expression regulation involving noncanonical, cap-independent translation of a select group of mRNAs. This is driven by death-associated protein 5 (DAP5/eIF4G2/NAT1), a translation initiation factor mediating IRES-dependent translation. We found that the DAP5 knockdown from human ESCs (hESCs) resulted in persistence of pluripotent gene expression, delayed induction of differentiation-associated genes in different cell lineages, and defective embryoid body formation. The latter involved improper cellular organization, lack of cavitation, and enhanced mislocalized apoptosis. RNA sequencing of polysome-associated mRNAs identified candidates with reduced translation efficiency in DAP5-depleted hESCs. These were enriched in mitochondrial proteins involved in oxidative respiration, a pathway essential for differentiation, the significance of which was confirmed by the aberrant mitochondrial morphology and decreased oxidative respiratory activity in DAP5 knockdown cells. Further analysis identified the chromatin modifier HMGN3 as a cap-independent DAP5 translation target whose knockdown resulted in defective differentiation. Thus, DAP5-mediated translation of a specific set of proteins is critical for the transition from pluripotency to differentiation, highlighting the importance of capindependent translation in stem cell fate decisions.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cap-independent translation by DAP5 controls cell fate decisions in human embryonic stem cells

et al. 2016

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“…The evolutionary conservation of oligo(U) sequences within TLs, as well as the cellular roles of the genes containing them, suggests that differential mRNA recognition by eIF4G plays a role in responses to cellular stimuli in yeast. Intriguingly, a recent screen for sequences promoting capindependent translation in human cells (Weingarten-Gabbay et al 2016) discovered oligo(U) sequences among the most potent stimulators. Although the basis for this activity was not determined, direct binding of eIF4G is sufficient to promote efficient cap-independent initiation (De Gregorio et al 1999).…”

Section: Discussionmentioning

confidence: 99%

Translation initiation factor eIF4G1 preferentially binds yeast transcript leaders containing conserved oligo-uridine motifs

Zinshteyn

Rojas-Durán

Gilbert

2017

RNA

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Translational control of gene expression plays essential roles in cellular stress responses and organismal development by enabling rapid, selective, and localized control of protein production. Translational regulation depends on context-dependent differences in the protein output of mRNAs, but the key mRNA features that distinguish efficiently translated mRNAs are largely unknown. Here, we comprehensively determined the RNA-binding preferences of the eukaryotic initiation factor 4G (eIF4G) to assess whether this core translation initiation factor has intrinsic sequence preferences that may contribute to preferential translation of specific mRNAs. We identified a simple RNA sequence motif-oligo-uridine-that mediates high-affinity binding to eIF4G in vitro. Oligo(U) motifs occur naturally in the transcript leader (TL) of hundreds of yeast genes, and mRNAs with unstructured oligo(U) motifs were enriched in immunoprecipitations against eIF4G. Ribosome profiling following depletion of eIF4G in vivo showed preferentially reduced translation of mRNAs with long TLs, including those that contain oligo(U). Finally, TL oligo(U) elements are enriched in genes with regulatory roles and are conserved between yeast species, consistent with an important cellular function. Taken together, our results demonstrate RNA sequence preferences for a general initiation factor, which cells potentially exploit for translational control of specific mRNAs.

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“…The possibility that some circRNAs are translatable is further exemplified by a recent systematic discovery that thousands of novel cap-independent translation sequences are found in the human genome. 52 Moreover, circular RNA has been reported to be translated in living human cells without any translational elements by a rolling circle amplification (RCA) mechanism. 53 Nevertheless, direct evidence of the translation of endogenous circRNAs has not been found yet.…”

Section: Transcription or Splicing Regulationmentioning

confidence: 99%

The emerging role and clinical implication of human exonic circular RNA

Lyu

Huang

2016

RNA Biology

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Circular RNA from backspliced exons (or exonic circular RNA, circRNA) is a type of covalently closed noncolinear RNA that was recently rediscovered in eukaryotes. Although circRNAs are often expressed at low levels, emerging evidence indicates that many circRNAs are linked to physiological development and various diseases. Notably, circRNAs have been shown to serve as oncogenic stimuli or tumor suppressors in cancer. circRNAs may regulate gene expression through different mechanisms. In addition, circRNAs have been shown to be useful as biomarkers of diseases due to their stability, specific expression and relation to diseases both in cells and in extracellular fluid. This review summarizes current knowledge of human circRNAs and discusses the emerging role and clinical implication of these multifarious transcripts.

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Systematic discovery of cap-independent translation sequences in human and viral genomes

Cited by 284 publications

References 58 publications

Cap-independent translation by DAP5 controls cell fate decisions in human embryonic stem cells

Cap-independent translation by DAP5 controls cell fate decisions in human embryonic stem cells

Translation initiation factor eIF4G1 preferentially binds yeast transcript leaders containing conserved oligo-uridine motifs

The emerging role and clinical implication of human exonic circular RNA

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