Global Regulation of Alternative RNA Splicing by the SR-Rich Protein RBM39
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE86846 | GEO | 2016/09/13
SECONDARY ACCESSION(S): PRJNA342707
REPOSITORIES: GEO
Similar Datasets
Project description:RBM39 is extensively involved in alternative splicing of RNA and helps regulate transcript levels. RBM39 may modulate alternative splicing similarly to U2AF65 by either directly binding to RNA or recruiting other splicing factors, such as U2AF65.
2017-07-20 | GSE101631 | GEO
Project description:We report a comprehensive analysis of alterations in gene expression and alternative splicing upon RBM39 depletion and rescue in HeLa cells.
2023-06-19 | GSE202134 | GEO
Project description:Characterization of RNA processing events dependent on U2AF-related proteins PUF60 and RBM39. PUF60 (poly-U-binding factor 60 kDa, also known as FIR, Hfp or Ro-bp1) is a splicing factor homologous to the 65 kD subunit of the auxiliary factor of U2 small nuclear ribonucleoprotein (U2AF65). PUF60 has two central RNA recognition motifs and a C-terminal U2AF homology motif (UHM), but lacks the N terminal arginine/serine-rich (RS) and UHM ligand motif (ULM) domains present in U2AF65. PUF60 activity, in conjunction with U2AF, facilitates the association of U2 snRNP with the pre-mRNA. PUF60 and U2AF65 can bind SF3b155 ULMs simultaneously and noncompetitively. RBM39 (also known as CAPERα, HCC1, FSAP59 or RNPC2) is an RNA processing factor and a hormone-dependent transcriptional coactivator. RBM39 domain structure is similar to PUF60, except for the extra N-terminal RS domain with unknown function. To understand function of the two proteins on a genome-wide scale, each protein was individually depleted from human embryonic kidney cell line 293 using RNAi to systematically characterize the PUF60- and RBM39-dependent exon usage.
2018-05-25 | E-MTAB-6010 | biostudies-arrayexpress
Project description:Indisulam selectively bridges splicing factor RBM39 to DCAF15 for proteasomal degradation. However, clinical trials indicate that patient stratification based upon the mechanism of action of indisulam may be required to achieve the best response. Here we show that neuroblastoma, a MYC-driven cancer characterized by splicing dysregulation, requires RBM39 for survival, expresses high levels of DCAF15 among different solid tumor lineages, and is the most sensitive cancer lineage to indisulam that achieves therapeutic effect by specifically targeting RBM39 in neuroblastoma. Genetic depletion or proteasomal degradation of RBM39 by indisulam induces drastic splicing event changes in neuroblastoma cells. Through specifically targeting RBM39, indisulam induces exceptional tumor response in multiple high-risk neuroblastoma models. Collectively we demonstrate that high RBM39 dependency and high-level expression of DCAF15 provide indisulam a more efficacious therapeutic window to treating high-risk neuroblastoma.
2021-11-24 | GSE164504 | GEO
Project description:Indisulam selectively bridges splicing factor RBM39 to DCAF15 for proteasomal degradation. However, clinical trials indicate that patient stratification based upon the mechanism of action of indisulam may be required to achieve the best response. Here we show that neuroblastoma, a MYC-driven cancer characterized by splicing dysregulation, requires RBM39 for survival, expresses high levels of DCAF15 among different solid tumor lineages, and is the most sensitive cancer lineage to indisulam that achieves therapeutic effect by specifically targeting RBM39 in neuroblastoma. Genetic depletion or proteasomal degradation of RBM39 by indisulam induces drastic splicing event changes in neuroblastoma cells. Through specifically targeting RBM39, indisulam induces exceptional tumor response in multiple high-risk neuroblastoma models. Collectively we demonstrate that high RBM39 dependency and high-level expression of DCAF15 provide indisulam a more efficacious therapeutic window to treating high-risk neuroblastoma.
2021-11-24 | GSE164505 | GEO
Project description:The U2AF heterodimer has been well studied for its role in defining functional 3M-bM-^@M-^Y splice sites in pre-mRNA splicing, but many fundamental questions still remain unaddressed regarding the function of U2AF in mammalian genomes. Through genome-wide analysis of U2AF-RNA interactions, we report that U2AF has the capacity to directly define ~88% of functional 3M-bM-^@M-^Y splice sites in the human genome, but numerous U2AF binding events also occur in intronic locations. Mechanistic dissection reveals that upstream intronic binding events interfere with the immediate downstream 3M-bM-^@M-^Y splice site associated with either the alternative exon to cause exon skipping or with the competing constitutive exon to induce exon inclusion. We further demonstrate partial functional impairment with mutations in U2AF35, but not U2AF65, in regulated splicing. These findings reveal the genomic function and regulatory mechanism of U2AF in both normal and disease states. Examination of U2AF heterodimer regulated splicing in Hela cells with CLIP-seq (U2AF65), paired-end RNA-seq (si-NC and si-U2AF65) and RASL-seq (respective three biological replicates of WT, si-NC, si-U2AF65, si-U2AF35, si-NC + pcDNA3.0, si-U2AF65 + pcDNA3.0, and si-U2AF65 + Flag-U2AF35)
2014-10-08 | E-GEOD-61603 | biostudies-arrayexpress
Project description:The investigational drugs E7820, indisulam and tasisulam (aryl-sulfonamides) promote the degradation of the splicing factor RBM39 in a proteasome and CRL4DCAF15 ubiquitin ligase-dependent mechanism, however the molecular details of this activity remain elusive. Here we present the cryo-EM structure of DDB1-DCAF15-DDA1 bound to RBM39 and E7820 at 4.4 Å resolution, together with crystal structures of engineered subcomplexes. We show that DCAF15 adopts a novel fold stabilized by DDA1, and that extensive protein-protein contacts between the ligase and substrate mitigate the low affinity interaction between aryl-sulfonamides and DCAF15. Our data demonstrates how aryl-sulfonamides neo-functionalize a shallow, non-conserved pocket on DCAF15 to selectively bind and degrade RBM39 and RBM23 without the requirement for a high affinity ligand, which has broad implications for the de novo discovery of molecular glue degraders.
2019-07-10 | PXD014536 | Pride
Project description:Alternative splicing is a key process underlying the evolution of increased proteomic and functional complexity and is especially prevalent in the mammalian nervous system. However, the factors and mechanisms governing nervous system-specific alternative splicing are not well understood. Through a genome-wide computational and expression profiling strategy, we have identified a tissue- and vertebrate-restricted Ser/Arg (SR)-repeat splicing factor, the neural-specific SR-related protein of 100 kDa (nSR100). We show that nSR100 regulates an extensive network of brain-specific alternative exons enriched in genes that function in neural cell differentiation. nSR100 acts by increasing the levels of the neural/brain-enriched polypyrimidine tract binding protein and by interacting with its target transcripts. Disruption of nSR100 prevents neural cell differentiation in cell culture and in the developing zebrafish. Our results thus reveal a critical neural-specific alternative splicing regulator, the evolution of which has contributed to increased complexity in the vertebrate nervous system. A microarray platform to profile alternative splicing levels for 8714 cassette-type alternative exons across a diverse spectrum of mouse tissues.
2010-05-15 | E-GEOD-16187 | biostudies-arrayexpress
Project description:Ovarian high-grade serous carcinoma (HGSC) is the most common and lethal subtype of ovarian cancer with limited therapeutic options. In recent years, PARP inhibitors have demonstrated significant clinical benefits, especially in patients with BRCA1/2 mutations. However, acquired drug resistance and relapse is a major challenge. Therapies disrupting the spliceosome alter cancer transcriptomes and have shown potential to improve PARP inhibitor response. Indisulam (E7070) has been identified as a molecular glue that brings splicing factor RBM39 and DCAF15 E3 ubiquitin ligase in close proximity. Exposure to indisulam induces RBM39 proteasomal degradation through DCAF15-mediated polyubiquitination and subsequent RNA splicing defects. In this study, we demonstrate that loss of RBM39 induces splicing errors in DNA damage repair genes in ovarian cancer, leading to increased sensitivity to PARP inhibitors such as olaparib. Indisulam synergized with olaparib in multiple in vitro models of ovarian cancer regardless of PARP inhibitor sensitivity and improved olaparib response in mice bearing PARP inhibitor-resistant tumors. DCAF15 expression, but not BRCA1/2 mutational status, was essential for the synergy between indisulam and olaparib, suggesting that the combination therapy may benefit patients irrespective of their BRCA1/2 status. These findings demonstrate that combining RBM39 degraders and PARP inhibitors is a promising therapeutic approach to improving PARP inhibitor response in ovarian HGSC
2023-01-22 | GSE223011 | GEO
Project description:Circular RNA (circRNA) is a group of RNA family generated by RNA circularization, which was discovered ubiquitously across different cancers. However, the internal structure of circRNA is hard to be determined since of the alternative splicing happened in exons and introns of circRNA and the cancer-specific alternative splicing of circRNA is less to be identified. Here we proposed a custom tool CircSplice, which could identify internal alternative splicing of circRNA and compare the differential splicing between samples. By applying CircSplice in ccRCC, we identified cancer-specific alternative splicing (AS) events belong to circRNAs in ccRCC. We further confirmed the existence of alternative splicing events in circRNAs by RT-PCR. This study is the first exploration of cancer-specific alternative splicing in circRNAs, which helps researchers to better understand potential functions of splicing of circRNAs in cancers.
2019-03-11 | GSE124453 | GEO