Effect of mutation in U2AF1 on splicing
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ABSTRACT:
PROVIDER: PRJNA1206089 | ENA |
REPOSITORIES: ENA
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Project description:SF3B1 is the most frequently mutated splicing factor in cancer. Such mutations cause missplicing by promoting aberrant 3' splice site usage; however, how this occurs mechanistically remains controversial. To address this issue, we employed a computational screen of 600 splicing-related proteins to identify those whose reduced expression recapitulates mutant SF3B1-induced splicing dysregulation. Strikingly, our analysis reveals only two proteins whose knockdown or knockout reproduces this effect. Extending our previous findings, loss of the G-patch protein SUGP1 recapitulates almost all splicing defects induced by SF3B1 hotspot mutations. Unexpectedly, loss of the RNA helicase Aquarius (AQR) reproduces ∼40% of these defects. However, we find that AQR knockdown causes significant SUGP1 missplicing and reduced SUGP1 levels, suggesting that AQR loss reproduces mutant SF3B1 splicing defects only indirectly. This study advances our understanding of missplicing caused by oncogenic SF3B1 mutations and highlights the fundamental role of SUGP1 in this process.
2025-07-03 | GSE285785 | GEO
Project description:Hotspot mutations in the spliceosomal component gene SF3B1 underpin a number of cancers and have a neomorphic function leading to global disruption of canonical splicing and aberrant splicing of hundreds of transcripts. However, the functional consequences of this misplicing and resultant genetic vulnerabilities imposed by these events are poorly understood. Through a synthetic-lethal approach we identify that SF3B1 mutant cells are selectively sensitive to PARP inhibitors. This vulnerability is preserved across multiple cell line and patent derived tumour models, independent of SF3B1 hotspot mutation and is manifested both in vitro and in vivo. These data provide the pre-clinical and mechanistic rationale for assessing SF3B1 mutations as a biomarker of single-agent PARP inhibitor response in a new patient population and may extend the clinical utility of these agents beyond BRCA mutated cancers.
2023-04-19 | PXD019046 | Pride
Project description:SF3B1 is the most frequently mutated RNA splicing factor in cancer, including in ~25% of myelodysplastic syndromes (MDS) patients. SF3B1-mutated MDS, which is strongly associated with ringed sideroblast morphology, is characterized by ineffective erythropoiesis, leading to severe, often fatal, anemia. However, functional evidence linking SF3B1 mutations to the anemia described in MDS patients harboring this genetic aberration is weak, and the underlying mechanism is completely unknown. Using isogenic SF3B1 wild-type and mutant cell lines, normal human CD34 cells and MDS patient cells, we define a previously unrecognized role of the kinase MAP3K7, encoded by a known mutant SF3B1-targeted transcript, in controlling proper terminal erythroid differentiation, and show how MAP3K7 missplicing leads to the anemia characteristic of SF3B1-mutated MDS, although not to ringed sideroblast formation. We found that p38 MAPK is deactivated in SF3B1 mutant isogenic and patient cells and that MAP3K7 is an upstream positive effector of p38 MAPK. We demonstrate that disruption of this MAP3K7-p38 MAPK pathway leads to premature downregulation of GATA1, a master regulator of erythroid differentiation, and that this is sufficient to trigger accelerated differentiation, erythroid hyperplasia and ultimately apoptosis. Our findings thus define the mechanism leading to the severe anemia found in MDS patients harboring SF3B1 mutations.
2021-11-06 | GSE187356 | GEO
Project description:SF3B1, which encodes an essential spliceosomal protein, is frequently mutated in myelodysplastic syndromes (MDS) and many cancers. However, the defect of mutant SF3B1 is unknown. Here, we analyzed RNA-sequencing data from MDS patients and confirmed that SF3B1 mutants use aberrant 3' splice sites. To elucidate the underlying mechanism, we purified complexes containing either wild-type or the hotspot K700E mutant SF3B1, and found that levels of a poorly studied spliceosomal protein, SUGP1, were reduced in mutant spliceosomes. Strikingly, SUGP1 knockdown completely recapitulated the splicing errors, whereas SUGP1 overexpression drove the protein, which our data suggests plays an important role in branchsite recognition, into the mutant spliceosome and partially rescued splicing. Other hotspot SF3B1 mutants showed similar altered splicing and diminished interaction with SUGP1. Our study demonstrates that SUGP1 loss is the sole defect of mutant SF3B1 spliceosomes and, since this defect can be rescued, suggests possibilities for therapeutic intervention.
2019-07-24 | GSE128805 | GEO
Project description:Engineering oncogenic hotspot mutations on SF3B1 via CRISPR-directed PRECIS mutagenesis
| PRJNA964746 | ENA
Project description:Mutations in the core RNA splicing factor SF3B1 are prevalent in leukemias and uveal melanoma, but also recurrent in epithelial malignancies such as breast cancer. Whereas hotspot mutations in SF3B1 alter hematopoietic differentiation, whether SF3B1 mutations contribute to epithelial cancer development and progression is unknown. Here, we identify that SF3B1 mutations in mammary epithelial and breast cancer cells induce a recurrent pattern of aberrant splicing leading to activation of AKT and NF-kB, enhanced cell migration, and accelerated tumorigenesis. Transcriptomic analysis of human cancer specimens, MMTV-cre Sf3b1K700E/WT mice, and isogenic mutant cell lines identified hundreds of aberrant 3’ splice sites induced by mutant SF3B1, a portion of which were breast-specific. Across mouse and human tumors, mutant SF3B1 promoted aberrant splicing (dependent on aberrant branchpoints as well as pyrimidines downstream of the aberrant branchpoint) and consequent suppression of PPP2R5A and MAP3K7, critical negative regulators of AKT and NF-kB. Coordinate activation of NF-kB and AKT signaling was observed in the knock-in models, leading to accelerated cell migration and tumor development in combination with mutant PIK3CA but also hypersensitizing cells to AKT kinase inhibitors. These data identify mutations in SF3B1 as drivers of breast tumorigenesis and reveal unique vulnerabilities in cancers harboring them.
2021-01-05 | GSE145471 | GEO
Project description:SF3B1 is the most frequently mutated splicing factor in cancer. Mechanistically, such mutations cause missplicing by promoting aberrant 3' splice site usage; however, how this occurs remains controversial. To address this issue, we employed a computational screen of 600 splicing-related proteins to identify those whose reduced expression recapitulated mutant SF3B1 splicing dysregulation. Strikingly, our analysis revealed only two proteins whose loss reproduced this effect. Extending our previous findings, loss of the G-patch protein SUGP1 recapitulated almost all splicing defects induced by SF3B1 hotspot mutations. Unexpectedly, loss of the RNA helicase Aquarius (AQR) reproduced ~40% of these defects. However, we found that AQR knockdown caused significant SUGP1 missplicing and reduced protein levels, suggesting that AQR loss reproduced mutant SF3B1 splicing defects only indirectly. This study advances our understanding of missplicing caused by oncogenic SF3B1 mutations, and highlights the fundamental role of SUGP1 in this process.
| S-EPMC11870612 | biostudies-literature
Project description:Recurrent mutations in the spliceosome are observed in several human cancers but their functional and therapeutic significance remain elusive. SF3B1, the most frequently mutated component of the spliceosome in cancer, is involved in the recognition of the branch point sequence (BPS) during selection of the 3’ splice site (ss) in RNA splicing. Here, we report that common and tumor-specific splicing aberrations are induced by SF3B1 mutations and establish aberrant 3’ ss selection as the most frequent splicing defect. Strikingly, mutant SF3B1 utilizes a BPS that differs from that used by wild-type SF3B1 and requires the canonical 3’ ss to enable aberrant splicing during the second step. Approximately 50% of the aberrantly spliced mRNAs are subjected to nonsense-mediated decay resulting in downregulation of gene and protein expression. These findings ascribe functional significance to the consequences of SF3B1 mutations in cancer. 72 samples, including two sets of patient data and cell lines with two additional technical replicates each
2015-09-08 | E-GEOD-72790 | biostudies-arrayexpress
Project description:SF3B1 mutant-induced missplicing of MAP3K7 causes anemia in myelodysplastic syndromes
| PRJNA777473 | ENA
Project description:To engineer novel SF3B1 mutant cell lines, we developed a methodology called PRECIS to install the pathogenic K700E mutation. We used this method to engineer CLL cell lines HG-3 and MEC-1 with the SF3B1 K700E mutation and then carried out RNA-seq.
2024-08-28 | GSE231387 | GEO