Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA312116 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR3169710_1.fastq.gz | Fastqsanger.gz | |||
| SRR3169710_2.fastq.gz | Fastqsanger.gz | |||
| SRR3169720_1.fastq.gz | Fastqsanger.gz | |||
| SRR3169720_2.fastq.gz | Fastqsanger.gz | |||
| SRR3169711_1.fastq.gz | Fastqsanger.gz |
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Project description:A multi-subunit exosome complex is a major eukaryotic exoribonuclease that in the cytoplasm requires the SKI complex for activity. In yeast, SKI forms a heterotetramer and delivers RNA substrates directly into the exosome channel. Such cooperation requires Ski7 protein, which links the exosome and SKI complexes. However, since the human genome does not encode an orthologue of the yeast Ski7, the factor mediating SKI and exosome linkage in human cells is unknown. Proteomic analysis revealed that the human cytoplasmic exosome interacts with HBS1LV3, a protein encoded by a newly discovered short splicing isoform of HBS1L. HBS1LV3 recruits the SKI complex to the exosome. In contrast, the canonical HBS1L variant, HBS1LV1, acting as a ribosome dissociation factor, does not associate with the exosome and instead interacts with the mRNA surveillance factor PELOTA. HBS1LV3 contains a new domain of unknown structure with the short linear motif RxxxFxxxL, which is responsible for exosome binding, and may interact with the exosome core subunit RRP43 in way that resembles the association between Rrp6 RNase and Rrp43 in yeast. Depletion of HBS1LV3 and the SKI complex helicase SKI2W similarly affected the transcriptome by strongly upregulating a large number of genes. Moreover, following HBS1LV3 or SKI2W depletion the half-lives of representative upregulated mRNAs were increased, thus supporting the involvement of HBS1LV3 and SKI2W in the same mRNA degradation pathway. In contrast, HBS1LV1 depletion had little effect on transcriptome homeostasis. Our data indicate that human HBS1LV3 is the long-sought factor that links the exosome and SKI complexes to regulate cytoplasmic mRNA decay.
2017-02-15 | GSE77926 | GEO
Project description:Cytoplasmic degradation of eukaryotic mRNAs in 3’ to 5’ direction is catalyzed by the exosome complex together with the Ski complex and, in the yeast Saccharomyces cerevisiae, the Ski7 protein. This exosome-Ski-system also degrades ribosome-associated aberrant mRNAs lacking a stop codon, a pathway called non-stop-mRNA decay (NSD). However, the interplay between the Ski components and the ribosome is unknown. Here, we report that the Ski complex can associate with ribosomes in vitro and in vivo independently of Ski7. Ribosome profiling suggests that this association is important for NSD but also for general mRNA turnover. A cryo-electron microscopy structure reveals that the Ski complex binds near the mRNA entry site of the 40S subunit, facilitating the threading of the mRNA into the Ski2 helicase. Collectively, these results demonstrate an unanticipated role for the Ski complex in mRNA decay of ribosome-associated mRNAs, mediated by a direct interaction with the translation machinery.
2017-02-10 | GSE70259 | GEO
Project description:The RNA exosome is a key 3’-5’ exoribonuclease with evolutionary conserved structure and roles. Its cytosolic functions require the co-factors SKI7 and the Ski complex. Here we demonstrate by co-purification experiments that the ARM repeat protein RESURRECTION1 (RST1) and RST1 INTERACTING PROTEIN (RIPR) connect the cytosolic Arabidopsis RNA exosome to the Ski complex. rst1 and ripr mutants accumulate small RNAs many of which are quality control siRNAs (rqc-siRNAs) produced by the postranscriptional gene silencing (PTGS) machinery when mRNA degradation is compromised. Indeed, quasi identical small RNA populations are observed in mutants lacking the RRP45B/CER7 subunit of the core exosome. This biochemical and genetic evidence supports a physical and functional link between RST1, RIPR and the RNA exosome. Our data reveal the existence of additional cytosolic exosome co-factors besides the known SKI subunits. Interestingly, RST1 is not restricted to plants, as homologues with a similar domain architecture exist in animals, including humans.
2019-07-17 | PXD013435 | Pride
Project description:Delineating key HSC regulators is of significant interest for informing the treatment of hematologic malignancy. While HSC activity is enhanced by overexpression of SKI, the transforming growth factor-beta (TGFβ) signaling antagonist corepressor, its requirement in HSC is unknown. Here we reveal a profound defect in Ski-/- HSC fitness but not specification. Transcriptionally, Ski-/- HSC exhibited striking upregulation of TGFb superfamily signaling and splicing alterations. As these are both common aspects of myelodysplastic-syndrome (MDS) pathobiology with prognostic value, we investigated the role of SKI in MDS. A SKI-correlated gene signature defines a subset of low-risk MDS patients with active TGFβ signaling and deregulated RNA splicing (e.g. CSF3R). The apparent paradox of Ski-/- HSC sharing molecular aspects of MDS with elevated SKI-mRNA is resolved by miR-21 targeting of SKI in MDS. We conclude that miR-21-mediated loss of SKI contributes to early stage MDS pathogenesis by activating TGFβ signaling and alternative splicing while hindering HSC fitness.
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Project description:It is now clearly established that immune system can affect cancer response to therapy. However, the influence of tumor microenvironment on immune cells is not completely understood. In this respect, alternative splicing is increasingly described to affect immune system biology. Here, we showed that tumor microenvironment, by increasing alternative splicing events, induced the expression of an alternative isoform of the IRF1 transcription factor in Th1 cells. Furthermore, we also shown, in both mice and humans, that IRF1 alternative isoform alters IRF1 full form transcriptional activity on Il12rb1 promotor, resulting in decreased IFN-? secretion in Th1 cells. Thus, IRF1-short isoform increases in tumor microenvironment and to prevent this isoform appearance could potentiate Th1 cell antitumor effect.
2021-04-27 | GSE134853 | GEO
Project description:It is now clearly established that immune system can affect cancer response to therapy. However, the influence of tumor microenvironment on immune cells is not completely understood. In this respect, alternative splicing is increasingly described to affect immune system biology. Here, we showed that tumor microenvironment, by increasing alternative splicing events, induced the expression of an alternative isoform of the IRF1 transcription factor in Th1 cells. Furthermore, we also shown, in both mice and humans, that IRF1 alternative isoform alters IRF1 full form transcriptional activity on Il12rb1 promotor, resulting in decreased IFN-? secretion in Th1 cells. Thus, IRF1-short isoform increases in tumor microenvironment and to prevent this isoform appearance could potentiate Th1 cell antitumor effect.
2021-04-27 | GSE134851 | GEO
Project description:ADAM12 is an A Disintegrin And Metalloproteinases (ADAMs). It is composed of signaling sequence, prodomain, metalloproteinase, disintegrin, cysteine-rich, EGF-like, transmembrane domains, and a cytoplasmic tail. ADAM12 is highly expressed in multiple cancers and is a diagnostic and prognostic biomarker for the proliferation, migration, and invasion of cancer cells. ADAM12 has several isoforms resulted from splicing variants with different subcellular localization and biological functions. Two most important isoforms are the prototype membrane-anchored long isoform ADAM12L and the secreted short isoform ADAM12S. Both of them contain the N-terminal 704 amino acids while their C-termini are different with each other. ADAM12S has extra 34 amino acids at its C-terminus, which replace the 171-amino acid transmembrane and cytoplasmic tail in ADAM12L. In this work, we use immunoprecipitation and quantitative proteomics to identify the interacting proteins of the short form of ADAM12 (ADAM12S).
2022-02-28 | PXD009078 | Pride
Project description:The MYCN oncoprotein broadly binds promoters in a heterodimer with its partner protein MAX. MYCN also interacts with the nuclear exosome, a 3’-5’exoribonuclease complex, to facilitate progression through the S phase hinting at an RNA-centric function. Here we show that MYCN forms stable high molecular weight complexes with multiple RNA-binding proteins including the nuclear exosome. RNA-binding assays reveal that MYCN directly binds to thousands of predominantly intronic RNA sites via a short, highly conserved sequence motif termed MYCBoxI. Exosome depletion results in MYCN globally re-localizing from promoters to intronic RNAs. The vacant promoters are then occupied by the MXD transcription repressor protein MNT, which inhibits MYCN-dependent transcription. MYCN fosters the degradation of its bound introns via tight association with the nuclear exosome targeting complex (NEXT). Our data demonstrate that MYCN is an RNA-binding protein that controls RNA turnover and argue that the competition between MYCN’s RNA- and DNA-bound states links the dynamics of the MYCN/MAX/MXD network to mRNA processing.
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Project description:Human genetic studies have identified the neuronal RNA binding protein, Rbfox1, as a candidate gene for autism spectrum disorders. While Rbfox1 functions as a splicing regulator in the nucleus, it is also alternatively spliced to produce cytoplasmic isoforms. To investigate cytoplasmic Rbfox1, we knocked down Rbfox proteins in mouse neurons and rescued with cytoplasmic or nuclear Rbfox1. Transcriptome profiling showed that nuclear Rbfox1 rescued splicing changes induced by knockdown, whereas cytoplasmic Rbfox1 rescued changes in mRNA levels. iCLIP-seq of subcellular fractions revealed that in nascent RNA Rbfox1 bound predominantly to introns, while cytoplasmic Rbox1 bound to 3' UTRs. Cytoplasmic Rbfox1 binding increased target mRNA stability and translation, and overlapped significantly with miRNA binding sites. Cytoplasmic Rbfox1 target mRNAs were enriched in genes involved in cortical development and autism. Our results uncover a new Rbfox1 regulatory network and highlight the importance of cytoplasmic RNA metabolism to cortical development and disease. In this data set, we included the data from RNA-seq experiments. We performed RNA-seq to profile gene expression and splicing changes. The expression levels of Rbfox1 and Rbfox3 in cultured mouse hippocampal neurons were reduced by siRNAs. The reduction of Rbfox1 and 3 was rescued by expression of cytoplasmic or nuclear Rbfox1 splice isoform. The gene expression and splicing profiles were compared between different treatments. Eight samples were analyzed.
2015-12-10 | E-GEOD-71916 | biostudies-arrayexpress
Project description:The RNA exosome is a versatile ribonuclease. In the nucleoplasm of mammalian cells, it is assisted by its adaptors the Nuclear EXosome Targeting (NEXT) complex and the PolyA eXosome Targeting (PAXT) connection. Via its association with the ARS2 and ZC3H18 proteins, NEXT/exosome is recruited to capped and short unadenylated transcripts. Conversely, PAXT/exosome was considered to target longer and adenylated substrates via their poly(A) tails. Here, mutational analysis of the core PAXT component ZFC3H1 uncovers a separate branch of the PAXT pathway, which targets short adenylated RNAs and relies on a direct ARS2-ZFC3H1 interaction. We further demonstrate that similar acidic-rich short linear motifs of ZFC3H1 and ZC3H18 compete for a common ARS2 epitope. Consequently, while promoting NEXT function, ZC3H18 antagonizes PAXT activity. We suggest that this unprecedented organization of RNA decay complexes provides co-activation of NEXT and PAXT at loci with abundant production of short exosome substrates.
2023-09-26 | GSE212557 | GEO