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Cotranscriptional exon skipping in the genotoxic stress response

ABSTRACT: Pre-mRNA splicing is functionally coupled to transcription, and genotoxic stresses can enhance alternative exon inclusion by affecting elongating RNA polymerase II. We report here that various genotoxic stress inducers, including camptothecin, inhibit the interaction between EWS, an RNA polymerase II-associated factor, and YB-1, a spliceosome-associated factor. This results in the cotranscriptional skipping of several exons of the MDM2 gene encoding the main p53 ubiquitin-ligase. This reversible exon skipping participates in the timely regulation of MDM2 expression, and may contribute to the accumulation of p53 during stress exposure and its rapid shut off when stress is removed. Finally, a splicing-sensitive microarray identified numerous exons that are skipped in response to camptothecin and EWS/YB-1 depletion. These data demonstrate genotoxic stress-induced alteration of the communication between the transcriptional and splicing machineries, resulting in widespread exon skipping and playing a central role in the genotoxic stress response. 6 samples of MCF7 cells exposed to different treatments were analyzed: 3 x control_6 hours; 3 x camptothecin_6 hours.

ORGANISM(S): Homo sapiens

SUBMITTER: Sanchez Gabriel

PROVIDER: S-ECPF-GEOD-21840 | biostudies-other |

REPOSITORIES: biostudies-other

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Cotranscriptional exon skipping in the genotoxic stress response

Project description:Pre-mRNA splicing is functionally coupled to transcription, and genotoxic stresses can enhance alternative exon inclusion by affecting elongating RNA polymerase II. We report here that various genotoxic stress inducers, including camptothecin, inhibit the interaction between EWS, an RNA polymerase II-associated factor, and YB-1, a spliceosome-associated factor. This results in the cotranscriptional skipping of several exons of the MDM2 gene encoding the main p53 ubiquitin-ligase. This reversible exon skipping participates in the timely regulation of MDM2 expression, and may contribute to the accumulation of p53 during stress exposure and its rapid shut off when stress is removed. Finally, a splicing-sensitive microarray identified numerous exons that are skipped in response to camptothecin and EWS/YB-1 depletion. These data demonstrate genotoxic stress-induced alteration of the communication between the transcriptional and splicing machineries, resulting in widespread exon skipping and playing a central role in the genotoxic stress response. 6 samples of MCF7 cells exposed to different treatments were analyzed: 3 x control_6 hours; 3 x camptothecin_6 hours.

2010-06-09 | E-GEOD-21840 | biostudies-arrayexpress

Cotranscriptional exon skipping in the genotoxic stress response

2010-05-20 | GSE21840 | GEO

Exon skipping variations modulate stress-inducible inflammation

Project description:Psychological stress reactions can stimulate mammalian immune functions due to yet unknown mechanisms. We hypothesized that these involve massive post-stress alternative splicing modulations in peripheral blood mononuclear cells (PBMCs). RNA was extracted from PBMCs of BALB/C mice following unpredictable repeated foot shocks. Among the tested group, five mice exhibiting the maximal circulation glucocorticoids were selected for the stress group. PBMC RNA of 5 BALB/C mice served as the control group. Through linear regression analysis of all the reciprocal junction pairs represented on the microarrays and the Ensembl database, 496 alternative splicing events were detected. The stressed mice showed 65% exon skipping out of total splicing event changes compared to controls. The detected genes exhibited functional enrichment (through DAVID EASE analysis) in alternative splicing (47%), cellular response to stress (12%), lymphocyte activation (8%), stress-induced proteins (2%) and heat-shock-induced proteins (2%). Specifically, exon skipping modifications in the Hnrnph1 and CLK1 splicing-related transcripts were accompanied by stress-inducible inclusions in the immune response-related IRF-1 gene. Our findings demonstrate dependence on exon skipping and independence from glucocorticoid and innate immunity for the stress-inducible exacerbation of immunity and open new venues for preventing post-trauma inflammatory crisis.

2018-04-15 | GSE37856 | GEO

Natural Exon Skipping Sets the Stage for Exon Skipping as Therapy for Dystrophic Epidermolysis Bullosa.

Project description:Dystrophic epidermolysis bullosa (DEB) is a devastating blistering disease affecting skin and mucous membranes. It is caused by pathogenic variants in the COL7A1 gene encoding type VII collagen, and can be inherited dominantly or recessively. Recently, promising proof-of-principle has been shown for antisense oligonucleotide (AON)-mediated exon skipping as a therapeutic approach for DEB. However, the precise phenotypic effect to be anticipated from exon skipping, and which patient groups could benefit, is not yet clear. To answer these questions, we studied new clinical and molecular data on seven patients from the Dutch EB registry and reviewed the literature on COL7A1 exon skipping variants. We found that phenotypes associated with dominant exon skipping cannot be distinguished from phenotypes caused by other dominant DEB variants. Recessive exon skipping phenotypes are generally relatively mild in the spectrum of recessive DEB. Therefore, for dominant DEB, AON-mediated exon skipping is unlikely to ameliorate the phenotype. In contrast, the overall severity of phenotypes associated with recessive natural exon skipping pivots toward the milder end of the spectrum. Consequently, we anticipate AON-mediated exon skipping for recessive DEB caused by bi-allelic null variants should lead to a clinically relevant improvement of this devastating phenotype.

| S-EPMC6831832 | biostudies-literature

Exon skipping induced by cold stress in a potato invertase gene transcript.

Project description:We show that two invertase genes in potato, like most other plant invertase genes, include a very short second exon of 9 bp which encodes the central three amino acids of a motif highly conserved in invertases of diverse origin. This mini-exon is one of the smallest known in plants and pre-mRNA from these genes may be susceptible to alternative splicing, because of a potential requirement for specialized interaction with the splicing machinery to ensure correct processing for the production of a mature mRNA. No evidence of aberrant post-transcriptional processing was observed during normal invertase gene expression in potato. The fidelity of post-transcriptional processing of the pre-mRNA from one of the genes was perturbed by cold stress, resulting in the deletion of the mini-exon from some transcripts. This alternative splicing event occurred under cold stress in both leaf and stem, but was not induced by wounding. This adds an example of exon skipping and the induction of alternative processing by cold stress to the small number of transcripts which have been shown to exhibit alternative splicing in plants. The differential sensitivity of post-transcriptional processing to cold stress observed for the two transcripts examined will permit further dissection of the nucleotide sequence requirements for their accurate splicing.

| S-EPMC145944 | biostudies-other

Exon-Skipping in Duchenne Muscular Dystrophy.

Project description:Duchenne muscular dystrophy (DMD) is a devastating, rare disease. While clinically described in the 19th century, the genetic foundation of DMD was not discovered until more than 100 years later. This genetic understanding opened the door to the development of genetic treatments for DMD. Over the course of the last 30 years, the research that supports this development has moved into the realm of clinical trials and regulatory drug approvals. Exon skipping to therapeutically restore the frame of an out-of-frame dystrophin mutation has taken center stage in drug development for DMD. The research reviewed here focuses on the clinical development of exon skipping for the treatment of DMD. In addition to the generation of clinical treatments that are being used for patient care, this research sets the stage for future therapeutic development with a focus on increasing efficacy while providing safety and addressing the multi-systemic aspects of DMD.

| S-EPMC8673534 | biostudies-literature

Conserved sequence elements associated with exon skipping.

Project description:One of the major forms of alternative splicing, which generates multiple mRNA isoforms differing in the precise combinations of their exon sequences, is exon skipping. While in constitutive splicing all exons are included, in the skipped pattern(s) one or more exons are skipped. The regulation of this process is still not well understood; so far, cis- regulatory elements (such as exonic splicing enhancers) were identified in individual cases. We therefore set to investigate the possibility that exon skipping is controlled by sequences in the adjacent introns. We employed a computer analysis on 54 sequences documented as undergoing exon skipping, and identified two motifs both in the upstream and downstream introns of the skipped exons. One motif is highly enriched in pyrimidines (mostly C residues), and the other motif is highly enriched in purines (mostly G residues). The two motifs differ from the known cis-elements present at the 5' and 3' splice site. Interestingly, the two motifs are complementary, and their relative positional order is conserved in the flanking introns. These suggest that base pairing interactions can underlie a mechanism that involves secondary structure to regulate exon skipping. Remarkably, the two motifs are conserved in mouse orthologous genes that undergo exon skipping.

| S-EPMC152795 | biostudies-literature

MET Exon 14 Alterations in Lung Cancer: Exon Skipping Extends Half-Life.

Project description:MET exon 14 alterations are a diverse group of mutations, many of which disrupt splice acceptor or donor sites leading to exon 14 skipping, impaired receptor degradation, and oncogenic transformation. These alterations are clinically targetable with MET-directed therapy. Clin Cancer Res; 22(12); 2832-4. ©2016 AACRSee related article by Tong et al., p. 3048.

| S-EPMC4911276 | biostudies-literature

Transcription-independent and -dependent p53-mediated apoptosis in response to genotoxic and non-genotoxic stress.

Project description:We previously reported that p53-mediated apoptosis is determined by severity of DNA damage, not by the level of p53, in doxorubicin-treated prostate cancer cells. In addition to doxorubicin, our results here indicated that camptothecin and bortezomib, which are a topoisomerase 1 poison and a 26?S proteasome inhibitor, respectively, could also induce apoptosis in a p53-dependent manner in prostate cancer. Then, we examined whether p53-mediated apoptosis induced by genotoxic and non-genotoxic stress occur in the same or a different way. By using dominant negative p53 to compete with wild-type p53 in transcription activity, we demonstrated that p53-mediated apoptosis in response to doxorubicin- or camptothecin-induced genotoxic stress is transcription-independent. In contrast, p53-mediated apoptosis from bortezomib-induced stress is transcription-dependent. Interestingly, we also found that doxorubicin-induced p21 expression is activated by p53 in transcription-dependent manner, while camptothecin-induced p21 expression is p53-independent. We then investigated the p53 ratio of nucleus to cytosol corresponding to low and high dose doxorubicin, camptothecin, or bortezomib treatment. The results suggested that p53 translocation from cytoplasm to nucleus actively drives cells toward apoptosis in either transcription-dependent or -independent manner for responding to non-genotoxic or genotoxic stress, respectively.

| S-EPMC6711993 | biostudies-literature

Variants affecting exon skipping contribute to complex traits.

Project description:DNA variants that affect alternative splicing and the relative quantities of different gene transcripts have been shown to be risk alleles for some Mendelian diseases. However, for complex traits characterized by a low odds ratio for any single contributing variant, very few studies have investigated the contribution of splicing variants. The overarching goal of this study is to discover and characterize the role that variants affecting alternative splicing may play in the genetic etiology of complex traits, which include a significant number of the common human diseases. Specifically, we hypothesize that single nucleotide polymorphisms (SNPs) in splicing regulatory elements can be characterized in silico to identify variants affecting splicing, and that these variants may contribute to the etiology of complex diseases as well as the inter-individual variability in the ratios of alternative transcripts. We leverage high-throughput expression profiling to 1) experimentally validate our in silico predictions of skipped exons and 2) characterize the molecular role of intronic genetic variations in alternative splicing events in the context of complex human traits and diseases. We propose that intronic SNPs play a role as genetic regulators within splicing regulatory elements and show that their associated exon skipping events can affect protein domains and structure. We find that SNPs we would predict to affect exon skipping are enriched among the set of SNPs reported to be associated with complex human traits.

| S-EPMC3486879 | biostudies-literature

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