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16 results on '"Tack, David C."'

1. eIF4A1-dependent mRNAs employ purine-rich 5’UTR sequences to activate localised eIF4A1-unwinding through eIF4A1-multimerisation to facilitate translation

Author

Schmidt, Tobias, Dabrowska, Adrianna, Waldron, Joseph A, Hodge, Kelly, Koulouras, Grigorios, Gabrielsen, Mads, Munro, June, Tack, David C, Harris, Gemma, McGhee, Ewan, Scott, David, Carlin, Leo M, Huang, Danny, Le Quesne, John, Zanivan, Sara, Wilczynska, Ania, and Bushell, Martin

Subjects
Genetics, 1.1 Normal biological development and functioning, Underpinning research, Generic health relevance, Infection, 5' Untranslated Regions, Protein Biosynthesis, Purines, RNA, Messenger, Humans, Eukaryotic Initiation Factor-4A, Environmental Sciences, Biological Sciences, Information and Computing Sciences, Developmental Biology
Abstract

Altered eIF4A1 activity promotes translation of highly structured, eIF4A1-dependent oncogene mRNAs at root of oncogenic translational programmes. It remains unclear how these mRNAs recruit and activate eIF4A1 unwinding specifically to facilitate their preferential translation. Here, we show that single-stranded RNA sequence motifs specifically activate eIF4A1 unwinding allowing local RNA structural rearrangement and translation of eIF4A1-dependent mRNAs in cells. Our data demonstrate that eIF4A1-dependent mRNAs contain AG-rich motifs within their 5'UTR which specifically activate eIF4A1 unwinding of local RNA structure to facilitate translation. This mode of eIF4A1 regulation is used by mRNAs encoding components of mTORC-signalling and cell cycle progression, and renders these mRNAs particularly sensitive to eIF4A1-inhibition. Mechanistically, we show that binding of eIF4A1 to AG-rich sequences leads to multimerization of eIF4A1 with eIF4A1 subunits performing distinct enzymatic activities. Our structural data suggest that RNA-binding of multimeric eIF4A1 induces conformational changes in the RNA resulting in an optimal positioning of eIF4A1 proximal to the RNA duplex enabling efficient unwinding. Our data proposes a model in which AG-motifs in the 5'UTR of eIF4A1-dependent mRNAs specifically activate eIF4A1, enabling assembly of the helicase-competent multimeric eIF4A1 complex, and positioning these complexes proximal to stable localised RNA structure allowing ribosomal subunit scanning.

Published
2023

5. Purine-rich RNA sequences in the 5’UTR site-specifically regulate eIF4A1-unwinding through eIF4A1-multimerisation to facilitate translation

Author

Schmidt, Tobias, primary, Dabrowska, Adrianna, additional, Waldron, Joseph A., additional, Hodge, Kelly, additional, Koulouras, Grigorios, additional, Gabrielsen, Mads, additional, Munro, June, additional, Tack, David C., additional, Harris, Gemma, additional, McGhee, Ewan, additional, Scott, David, additional, Carlin, Leo M., additional, Huang, Danny, additional, Le Quesne, John, additional, Zanivan, Sara, additional, Wilczynska, Ania, additional, and Bushell, Martin, additional

Published
2022
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6. Transcriptome-wide probing reveals RNA thermometers that regulate translation of glycerol permease genes in Bacillus subtilis

Author

Jolley, Elizabeth A., Yakhnin, Helen, Tack, David C., Babitzke, Paul, and Bevilacqua, Philip C.

Abstract

RNA structure regulates bacterial gene expression by several distinct mechanisms via environmental and cellular stimuli, one of which is temperature. While some genome-wide studies have focused on heat shock treatments and the subsequent transcriptomic changes, soil bacteria are less likely to experience such rapid and extreme temperature changes. Though RNA thermometers (RNATs) have been found in 5′ untranslated leader regions (5′ UTRs) of heat shock and virulence-associated genes, this RNA-controlled mechanism could regulate other genes as well. Using Structure-seq2 and the chemical probe dimethyl sulfate (DMS) at four growth temperatures ranging from 23°C to 42°C, we captured a dynamic response of the Bacillus subtilistranscriptome to temperature. Our transcriptome-wide results show RNA structural changes across all four temperatures and reveal nonmonotonic reactivity trends with increasing temperature. Then, focusing on subregions likely to contain regulatory RNAs, we examined 5′ UTRs to identify large, local reactivity changes. This approach led to the discovery of RNATs that control the expression of glpF(glycerol permease) and glpT(glycerol-3-phosphate permease); expression of both genes increased with increased temperature. Results with mutant RNATs indicate that both genes are controlled at the translational level. Increased import of glycerols at high temperatures could provide thermoprotection to proteins.

Published
2023
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12. Genome-wide RNA structurome reprogramming by acute heat shock globally regulates mRNA abundance.

Author

Zhao Su, Mengmeng Zhu, Tack, David C., Assmann, Sarah M., Yin Tang, Ritchey, Laura E., and Bevilacqua, Philip C.

Subjects
GENOMES, HEAT shock factors, RNA, DIMETHYL sulfate, THERMOMETERS
Abstract

The heat shock response is crucial for organism survival in natural environments. RNA structure is known to influence numerous processes related to gene expression, but there have been few studies on the global RNA structurome as it prevails in vivo. Moreover, how heat shock rapidly affects RNA structure genomewide in living systems remains unknown. We report here in vivo heat-regulated RNA structuromes. We applied Structure-seq chemical [dimethyl sulfate (DMS)] structure probing to rice (Oryza sativa L.) seedlings with and without 10 min of 42 °C heat shock and obtained structural data on >14,000 mRNAs. We show that RNA secondary structure broadly regulates gene expression in response to heat shock in this essential crop species. Our results indicate significant heatinduced elevation of DMS reactivity in the global transcriptome, revealing RNA unfolding over this biological temperature range. Our parallel Ribo-seq analysis provides no evidence for a correlation between RNA unfolding and heat-induced changes in translation, in contrast to the paradigm established in prokaryotes, wherein melting of RNA thermometers promotes translation. Instead, we find that heat-induced DMS reactivity increases correlate with significant decreases in transcript abundance, as quantified from an RNA-seq time course, indicating that mRNA unfolding promotes transcript degradation. The mechanistic basis for this outcome appears to be mRNA unfolding at both 5' and 3'-UTRs that facilitates access to the RNA degradation machinery. Our results thus reveal unexpected paradigms governing RNA structural changes and the eukaryotic RNA life cycle. [ABSTRACT FROM AUTHOR]

Published
2018
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15. mRNA structural elements immediately upstream of the start codon dictate dependence upon eIF4A helicase activity

Author

Waldron, Joseph A, Tack, David C, Ritchey, Laura E, Gillen, Sarah L, Wilczynska, Ania, Turro, Ernest, Bevilacqua, Philip C, Assmann, Sarah M, Bushell, Martin, and Le Quesne, John

Subjects
Hippuristanol, Translation, DMS, Polysome profiling, Codon, Initiator, G-quadruplexes, 3. Good health, Sterols, Translation initiation, Eukaryotic Initiation Factor-4A, MCF-7 Cells, Humans, eIF4A, RNA, Messenger, Structure-seq, RNA structure, 5' Untranslated Regions, Cancer
Abstract

BACKGROUND: The RNA helicase eIF4A1 is a key component of the translation initiation machinery and is required for the translation of many pro-oncogenic mRNAs. There is increasing interest in targeting eIF4A1 therapeutically in cancer, thus understanding how this protein leads to the selective re-programming of the translational landscape is critical. While it is known that eIF4A1-dependent mRNAs frequently have long GC-rich 5'UTRs, the details of how 5'UTR structure is resculptured by eIF4A1 to enhance the translation of specific mRNAs are unknown. RESULTS: Using Structure-seq2 and polysome profiling, we assess global mRNA structure and translational efficiency in MCF7 cells, with and without eIF4A inhibition with hippuristanol. We find that eIF4A inhibition does not lead to global increases in 5'UTR structure, but rather it leads to 5'UTR remodeling, with localized gains and losses of structure. The degree of these localized structural changes is associated with 5'UTR length, meaning that eIF4A-dependent mRNAs have greater localized gains of structure due to their increased 5'UTR length. However, it is not solely increased localized structure that causes eIF4A-dependency but the position of the structured regions, as these structured elements are located predominantly at the 3' end of the 5'UTR. CONCLUSIONS: By measuring changes in RNA structure following eIF4A inhibition, we show that eIF4A remodels local 5'UTR structures. The location of these structural elements ultimately determines the dependency on eIF4A, with increased structure just upstream of the CDS being the major limiting factor in translation, which is overcome by eIF4A activity.

16. mRNA structural elements immediately upstream of the start codon dictate dependence upon eIF4A helicase activity

Author

Waldron, Joseph A., Tack, David C., Ritchey, Laura E., Gillen, Sarah L., Wilczynska, Ania, Turro, Ernest, Bevilacqua, Philip C., Assmann, Sarah M., Bushell, Martin, and Le Quesne, John

Subjects
Hippuristanol, Translation, Research, DMS, Translation initiation, Polysome profiling, eIF4A, Structure-seq, RNA structure, G-quadruplexes, 3. Good health, Cancer
Abstract

Background: The RNA helicase eIF4A1 is a key component of the translation initiation machinery and is required for the translation of many pro-oncogenic mRNAs. There is increasing interest in targeting eIF4A1 therapeutically in cancer, thus understanding how this protein leads to the selective re-programming of the translational landscape is critical. While it is known that eIF4A1-dependent mRNAs frequently have long GC-rich 5′UTRs, the details of how 5′UTR structure is resculptured by eIF4A1 to enhance the translation of specific mRNAs are unknown. Results: Using Structure-seq2 and polysome profiling, we assess global mRNA structure and translational efficiency in MCF7 cells, with and without eIF4A inhibition with hippuristanol. We find that eIF4A inhibition does not lead to global increases in 5′UTR structure, but rather it leads to 5′UTR remodeling, with localized gains and losses of structure. The degree of these localized structural changes is associated with 5′UTR length, meaning that eIF4A-dependent mRNAs have greater localized gains of structure due to their increased 5′UTR length. However, it is not solely increased localized structure that causes eIF4A-dependency but the position of the structured regions, as these structured elements are located predominantly at the 3′ end of the 5′UTR. Conclusions: By measuring changes in RNA structure following eIF4A inhibition, we show that eIF4A remodels local 5′UTR structures. The location of these structural elements ultimately determines the dependency on eIF4A, with increased structure just upstream of the CDS being the major limiting factor in translation, which is overcome by eIF4A activity.

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