Global regulation of alternative RNA splicing by the SR-rich protein RBM39

Mai, Sanyue; Qu, Xiuhua; Li, Ping; Ma, Qingjun; Cao, Cheng; Li, Xuan

doi:10.1016/j.bbagrm.2016.06.007

Cited by 42 publications

(80 citation statements)

References 38 publications

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“…For each exon and each knockdown, we scored the "Splicing Index" and a "Splicing Change" value as the relative effect of the knockdown to the maximal possible increase in inclusion ( Fig 4B). Analyses of Splicing Changes demonstrated a globally positive effect of U2AF 65 , CAPERa, and PUF60 on exon inclusion but an inhibitory action of SPF45 in agreement with previous functional characterization of these factors [24,41,42] ( Fig 4C). U2AF 65 and CAPERa presented a statistically significant overlap among decreased inclusion events upon knockdown ( Fig 4D).…”

Section: Functional Relationship Of Capera and U2af 65 In Cassette Exsupporting

confidence: 91%

“…In our knockdown approach in HeLa cells, we observed a general function of U2AF 65 , CAPERa, and PUF60 to promote exon inclusion. In addition, correlation analyses pointed to a particular functional relationship between U2AF 65 and CAPERa in controlling exon cassette splicing, in agreement with a recent comparison of these splicing factors in MCF-7 cells [42]. An extensive analysis of splicing using RNA-Seq data in K562 cells confirmed the highest positive correlation between U2AF 65 and CAPERa and allowed to detect also a positive correlation of these two factors with PUF60 in agreement with redundancy and cooperativity of U2AF 65 and PUF60 for splicing in vitro [41].…”

Section: Correlation Between Uhmsfs In Splicing Regulationssupporting

confidence: 87%

“…We then compared the Splicing Changes for all the cassette exons in response to the different knockdowns ( Fig 4E). Spearman's correlation analyses of these data confirmed the particular relationship between U2AF 65 and CAPERa consistently with recent siRNA-mediated knockdown and RNA-Seq experiments [42].…”

Section: Functional Relationship Of Capera and U2af 65 In Cassette Exsupporting

confidence: 82%

“…We found a significant positive correlation of "Splicing Changes" upon knockdown of CAPERa and U2AF 65 with the DSPY scores ( Fig 4F, Spearman rho = 0.40, P = 1.6E-03 and rho = 0.33, P = 8.8E-03, respectively). To generalize these observations, we performed similar analyses using available RNA-Seq data for K562 [43], HeLa [44], MCF7 [42], and HEK293T [45] cells. We aligned reads to our library of sequences corresponding to 5,629 cassette exon inclusions and exclusions.…”

Section: Functional Relationship Of Capera and U2af 65 In Cassette Exmentioning

confidence: 98%

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U2 AF ⁶⁵ assemblies drive sequence‐specific splice site recognition

et al. 2019

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The essential splicing factor U2AF65 is known to help anchoring U2 snRNP at the branch site. Its C‐terminal UHM domain interacts with ULM motifs of SF3b155, an U2 snRNP protein. Here, we report a cooperative binding of U2AF65 and the related protein CAPERα to the multi‐ULM domain of SF3b155. In addition, we show that the RS domain of U2AF65 drives a liquid–liquid phase separation that is amplified by intronic RNA with repeated pyrimidine tracts. In cells, knockdown of either U2AF65 or CAPERα improves the inclusion of cassette exons that are preceded by such repeated pyrimidine‐rich motifs. These results support a model in which liquid‐like assemblies of U2AF65 and CAPERα on repetitive pyrimidine‐rich RNA sequences are driven by their RS domains, and facilitate the recruitment of the multi‐ULM domain of SF3b155. We anticipate that posttranslational modifications and proteins recruited in dynamical U2AF65 and CAPERα condensates may further contribute to the complex mechanisms leading to specific splice site choice that occurs in cells.

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Section: Functional Relationship Of Capera and U2af 65 In Cassette Exsupporting

confidence: 91%

Section: Correlation Between Uhmsfs In Splicing Regulationssupporting

confidence: 87%

Section: Functional Relationship Of Capera and U2af 65 In Cassette Exsupporting

confidence: 82%

Section: Functional Relationship Of Capera and U2af 65 In Cassette Exmentioning

confidence: 98%

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U2 AF ⁶⁵ assemblies drive sequence‐specific splice site recognition

et al. 2019

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“…RNA binding protein splicing network in AML, anticancer drug (splicing inhibitors) resistance [5] , mTOR signalling pathway [5,6] 10 CDK4 Amplificatio n oncogene…”

mentioning

confidence: 99%

Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15

Han

Goralski

Gaskill

et al. 2017

Science

502

542

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Indisulam is an aryl sulfonamide drug with selective anticancer activity. Its mechanism of action and the basis for its selectivity have so far been unknown. Here we show that indisulam promotes the recruitment of RBM39 (RNA binding motif protein 39) to the CUL4-DCAF15 E3 ubiquitin ligase, leading to RBM39 polyubiquitination and proteasomal degradation. Mutations in RBM39 that prevent its recruitment to CUL4-DCAF15 increase RBM39 stability and confer resistance to indisulam's cytotoxicity. RBM39 associates with precursor messenger RNA (pre-mRNA) splicing factors, and inactivation of RBM39 by indisulam causes aberrant pre-mRNA splicing. Many cancer cell lines derived from hematopoietic and lymphoid lineages are sensitive to indisulam, and their sensitivity correlates with DCAF15 expression levels. Two other clinically tested sulfonamides, tasisulam and chloroquinoxaline sulfonamide, share the same mechanism of action as indisulam. We propose that DCAF15 expression may be a useful biomarker to guide clinical trials of this class of drugs, which we refer to as SPLAMs (splicing inhibitor sulfonamides).

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The RNA‐binding protein caper is required for sensory neuron development in Drosophila melanogaster

Olesnicky

Bono

Bell

et al. 2017

Developmental Dynamics

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Background Alternative splicing mediated by RNA-binding proteins (RBPs) is emerging as a fundamental mechanism for the regulation of gene expression. Alternative splicing has been shown to be a widespread phenomenon that facilitates the diversification of gene products in a tissue specific manner. Although defects in alternative splicing are rooted in many neurological disorders, only a small fraction of splicing factors have been investigated in detail. Results We find that the splicing factor Caper is required for the development of multiple different mechanosensory neuron subtypes at multiple life stages in Drosophila melanogaster. Disruption of Caper function causes defects in dendrite morphogenesis of larval dendrite arborization neurons, neuronal positioning of embryonic proprioceptors, as well as the development and maintenance of adult mechanosensory bristles. Additionally, we find that Caper dysfunction results in aberrant locomotor behavior in adult flies. Transcriptome-wide analyses further support a role for Caper in alternative isoform regulation of genes that function in neurogenesis. Conclusions Our results provide the first evidence for a fundamental and broad requirement for the highly conserved splicing factor Caper in the development and maintenance of the nervous system and provide a framework for future studies on the detailed mechanism of Caper mediated RNA regulation.

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Global regulation of alternative RNA splicing by the SR-rich protein RBM39

Cited by 42 publications

References 38 publications

U2 AF ⁶⁵ assemblies drive sequence‐specific splice site recognition

U2 AF ⁶⁵ assemblies drive sequence‐specific splice site recognition

Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15

The RNA‐binding protein caper is required for sensory neuron development in Drosophila melanogaster

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Global regulation of alternative RNA splicing by the SR-rich protein RBM39

Cited by 42 publications

References 38 publications

U2 AF 65 assemblies drive sequence‐specific splice site recognition

U2 AF 65 assemblies drive sequence‐specific splice site recognition

Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15

The RNA‐binding protein caper is required for sensory neuron development in Drosophila melanogaster

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U2 AF ⁶⁵ assemblies drive sequence‐specific splice site recognition

U2 AF ⁶⁵ assemblies drive sequence‐specific splice site recognition