Splicing modulators elicit global translational repression by condensate-prone proteins translated from introns
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ABSTRACT:
PROVIDER: PRJNA530968 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8848243.fastq.gz | Fastqsanger.gz | |||
| SRR8848244.fastq.gz | Fastqsanger.gz | |||
| SRR8848245.fastq.gz | Fastqsanger.gz | |||
| SRR8848246.fastq.gz | Fastqsanger.gz | |||
| SRR8848247.fastq.gz | Fastqsanger.gz |
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Project description:Chemical splicing modulators that bind to the spliceosome have provided an attractive venue for cancer treatment. Splicing modulators induce accumulation and subsequent translation of a subset of intron-retained mRNAs. Yet, the biological effect of proteins containing translated intron sequences remains unclear. Here we identified a number of truncated proteins generated upon treatment with the splicing modulator spliceostatin A (SSA) using genome-wide ribosome profiling and bio-orthogonal non-canonical amino-acid tagging (BONCAT) mass spectrometry. A subset of these truncated proteins has intrinsically disordered regions, forms insoluble cellular condensates, and triggers the proteotoxic stress response through JNK phosphorylation, thereby inhibiting the mTORC1 pathway. In turn, this reduces global translation. These findings indicate that creating an overburden of condensate-prone proteins derived from introns represses translation and prevents further production of harmful truncated proteins. This mechanism appears to contribute to the antiproliferative and proapoptotic activity of splicing modulators.
2021-03-29 | GSE129305 | GEO
Project description:Chemical splicing modulators that bind to the spliceosome have provided an attractive avenue for cancer treatment. Splicing modulators induce accumulation and subsequent translation of a subset of intron-retained mRNAs. However, the biological effect of proteins containing translated intron sequences remains unclear. Here, we identify a number of truncated proteins generated upon treatment with the splicing modulator spliceostatin A (SSA) via genome-wide ribosome profiling and bio-orthogonal noncanonical amino acid tagging (BONCAT) mass spectrometry. A subset of these truncated proteins has intrinsically disordered regions, forms insoluble cellular condensates, and triggers the proteotoxic stress response through c-Jun N-terminal kinase (JNK) phosphorylation, thereby inhibiting the mTORC1 pathway. In turn, this reduces global translation. These findings indicate that creating an overburden of condensate-prone proteins derived from introns represses translation and prevents further production of harmful truncated proteins. This mechanism appears to contribute to the antiproliferative and proapoptotic activity of splicing modulators.
| S-EPMC8857039 | biostudies-literature
Project description:This SuperSeries is composed of the following subset Series:; GSE14383: Effects of chronic exposure of human bronchial epithelial cells to low doses of cigarette smoke condensate; GSE14385: Response of bronchial epithelial cells to low doses of cigarette smoke condensate and subsequent demethylation agent Experiment Overall Design: Refer to individual Series
2009-08-09 | E-GEOD-14461 | biostudies-arrayexpress
Project description:Mycbacterium tuberculosis was exposed to cigarette smoke condensate (CSC) in 7H9 dextrose culture media. The transcriptional response to cigarette smoke condensate was compared to that of exposure to the CSC diluent, DMSO..
2021-04-15 | GSE172041 | GEO
Project description:Removal of introns by pre-mRNA splicing is a critical and in some cases rate-limiting step in mammalian gene expression. Deep sequencing of mouse embryonic stem cell RNA revealed many specific internal introns that are significantly more abundant than the other introns within poly(A) selected transcripts; we classify these as “detained” introns (DIs). We identified thousands of DIs flanking both constitutive and alternatively spliced exons in human and mouse cell lines. Drug inhibition of Clk SR-protein kinase activity triggered rapid splicing changes in a specific set of DIs, about half of which showed increased splicing and half increased intron detention, altering the transcript pool of over 300 genes. These data suggest a widespread mechanism by which a nuclear detained pool of mostly processed pre-mRNAs can be rapidly mobilized in response to stress or homeostatic autoregulation. v6.5 mouse embryonic stem cells were untreated, treated with the Clk kinase inhibitor KH-CB19, or treated with DMSO as a negative control. Untreated cells were harvested and a single replicate was sequenced using a custom, ligation-based, stranded library preparation protocol. Treated cells were harvested at time 0 and at 2 hours post-treatment, and poly(A)-selected RNA-seq libraries were made from biological duplicates for each treatment/time, barcoded, and sequenced by strand-specific, paired-end sequencing using the Illumina TruSeq kit.
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Project description:Intron retention (IR) is an alternative splicing event where mRNAs containing unspliced introns are exported to the cytoplasm and then either translated, giving rise to new protein isoforms, or degraded via the nonsense-mediated decay pathway. However, unspliced introns are also seen in nuclear RNA. Some of these are spliced at a low rate but do eventually become fully spliced and their respective mRNAs exported, while others stay retained and are recognized by nuclear decay machineries. IR has been shown to be regulated during granulocyte and neuronal differentiation and in some cancers, and a subset of the nuclear retained introns, called detained introns, have been implicated in growth control pathways. Despite many findings on IR and its biological significance, it is still not clear whether an incompletely spliced intron observed is a true retained intron that is exported as an mRNA or is a product of slow splicing that remains in the nucleus. A better understanding is needed of the molecular events that reduce intron excision rate and determine the release of an RNA for export. We have found that some genes in mouse embryonic stem cells (mESCs) produce RNAs that are highly associated with the high molecular-weight nuclear pellet (chromatin), rather than the soluble nucleoplasm or cytoplasm. This chromatin-associated RNA is polyadenylated, usually contains one or more incompletely spliced introns, and is often extensively bound by polypyrimidine tract-binding protein 1 (PTBP1). We hypothesize that PTBP1 inhibits splicing of these introns, and this causes sequestration of the transcript on chromatin. We are studying the role of PTBP1 in inhibiting intron excision and anchoring RNAs in the nuclear and chromatin compartments of mESCs.
2020-11-18 | GSE159993 | GEO
Project description:Despite the high conservation of minor introns across eukaryotic supergroups, specific lineages have completely lost minor intron splicing, which has raised questions about their evolution and purpose. Addressing these questions requires identification of the introns that are affected by minor spliceosome inhibition. To this end, we applied principles of Linnaean taxonomy combined with position-weight matrices to produce five intron classes: minor, minor-like, hybrid, major-like and major. We classified introns across the genomes of 263 species of six eukaryotic supergroups, which can be viewed at the Minor Intron Database (MIDB). Transcriptomic analysis revealed that ~40% of the minor introns are responsive to minor spliceosome inhibition, while an additional 5% of the minor-like and hybrid introns are also affected. We propose that minor-like introns represent an intermediate in the conversion of minor to major introns and uncover the importance of a guanine at the -1 position of the 5’ splice site in facilitating this shift in spliceosome dependence. Finally, we find that minor introns are aberrantly spliced in fish and plants upon cold stress, thereby providing a potential explanation for their high degree of conservation in these lineages.
2024-07-01 | GSE216619 | GEO
Project description:Removal of introns by pre-mRNA splicing is a critical and in some cases rate-limiting step in mammalian gene expression. Deep sequencing of mouse embryonic stem cell RNA revealed many specific internal introns that are significantly more abundant than the other introns within poly(A) selected transcripts; we classify these as “detained” introns (DIs). We identified thousands of DIs flanking both constitutive and alternatively spliced exons in human and mouse cell lines. Drug inhibition of Clk SR-protein kinase activity triggered rapid splicing changes in a specific set of DIs, about half of which showed increased splicing and half increased intron detention, altering the transcript pool of over 300 genes. These data suggest a widespread mechanism by which a nuclear detained pool of mostly processed pre-mRNAs can be rapidly mobilized in response to stress or homeostatic autoregulation.
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Project description:Spliceosomal introns are ubiquitous non-coding RNAs typically destined for rapid debranching and degradation. Here, we describe 34 excised Saccharomyces cerevisiae introns that, although rapidly degraded in log-phase growth, accumulate as linear RNAs under either saturated-growth conditions or other stresses that cause prolonged inhibition of TORC1, a key integrator of growth signaling. Introns that become stabilized remain associated with components of the spliceosome and differ from other spliceosomal introns in having a short distance between their lariat branch point and 3´ splice site, which is necessary and sufficient for their stabilization. Deletion of these unusual introns is disadvantageous in saturated conditions and causes aberrantly high growth rates of yeast chronically challenged with the TORC1 inhibitor rapamycin. Reintroduction of native or engineered stable introns suppresses this aberrant rapamycin response. Thus, excised introns function within the TOR growth-signaling network of S. cerevisiae, and more generally, excised spliceosomal introns can have biological functions.
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