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Cancer-associated snaR-A noncoding RNA interacts with core splicing machinery and disrupts processing of mRNA subpopulations

ABSTRACT: RNA polymerase III (Pol III) transcription in cancer is linked with the emergence of snaR-A (small NF90-associated RNA isoform A), a hominid-specific ncRNA shown to enhance cell proliferation, migration, and invasion. Here, we investigate snaR-A-protein interactions to delineate its role as a putative driver of cancer progression. At the molecular level, we discover that snaR-A interacts with mRNA splicing factors, including SF3B2 - a core component of the U2 small nuclear ribonucleoprotein (snRNP) - and localizes to subnuclear foci enriched for splicing factors. Ectopic snaR-A overexpression leads to increased intron retention, a hallmark of inefficient splicing, whereas depletion of endogenous snaR-A reduces intron retention in mRNA subpopulations associated with 3’ intron-exon U2 snRNP residency and nuclear speckle proximity. We further show that high levels of snaR-A promotes cell migration in cells linked with increased intron retention, consistent with evidence supporting snaR-A as a negative prognostic factor in cancer. Taken together, these findings establish snaR-A as a molecular disruptor of splicing. We propose that snaR-A-related splicing disruption may phenocopy previously reported splicing defects and consequences attributed to mutations in U2 snRNP in cancer, eliciting an alternate, non-mutational pathway during tumorigenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE293548 | GEO | 2025/04/28

REPOSITORIES: GEO

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Similar Datasets

Cancer-associated snaR-A noncoding RNA interacts with core splicing machinery and disrupts processing of mRNA subpopulations II

Project description:RNA polymerase III (Pol III) transcription in cancer is linked with the emergence of snaR-A (small NF90-associated RNA isoform A), a hominid-specific ncRNA shown to enhance cell proliferation, migration, and invasion. Here, we investigate snaR-A-protein interactions to delineate its role as a putative driver of cancer progression. At the molecular level, we discover that snaR-A interacts with mRNA splicing factors, including SF3B2 - a core component of the U2 small nuclear ribonucleoprotein (snRNP) - and localizes to subnuclear foci enriched for splicing factors. Ectopic snaR-A overexpression leads to increased intron retention, a hallmark of inefficient splicing, whereas depletion of endogenous snaR-A reduces intron retention in mRNA subpopulations associated with 3’ intron-exon U2 snRNP residency and nuclear speckle proximity. We further show that high levels of snaR-A promotes cell migration in cells linked with increased intron retention, consistent with evidence supporting snaR-A as a negative prognostic factor in cancer. Taken together, these findings establish snaR-A as a molecular disruptor of splicing. We propose that snaR-A-related splicing disruption may phenocopy previously reported splicing defects and consequences attributed to mutations in U2 snRNP in cancer, eliciting an alternate, non-mutational pathway during tumorigenesis.

2025-04-28 | GSE286577 | GEO

Cancer-associated snaR-A noncoding RNA interacts with core splicing machinery and disrupts processing of mRNA subpopulations

Project description:RNA polymerase III (Pol III) activity in cancer is linked to the production of small noncoding (nc)RNAs that are otherwise silent in most tissues. snaR-A (small NF90-associated RNA isoform A) - a hominid-specific ncRNA shown to enhance cell proliferation, migration, and invasion - is a cancer-emergent Pol III product that remains largely uncharacterized despite promoting growth phenotypes. Here, we applied a combination of genomic and biochemical approaches to predict the biogenesis and subsequent protein interactions of snaR-A to better understand its role as a putative driver of cancer progression. By profiling the chromatin landscapes across a multitude of primary tumor types, we show that predicted snaR-A upregulation is broadly linked with unfavorable outcomes among cancer patients. At the molecular level, we unexpectedly discover widespread interactions between snaR-A and mRNA splicing factors, including SF3B2 - a core component of the U2 small nuclear ribonucleoprotein (snRNP). We find that SF3B2 levels are sensitive to high snaR-A abundance, and that depletion of snaR-A alone is sufficient to decrease intron retention levels across subpopulations of mRNA enriched for U2 snRNP occupancy. snaR-A sensitive genes are characterized by high GC content, close spatial proximity to nuclear bodies concentrated in pre-mRNA splicing factors, and functionally enriched for proteins involved in deacetylation and autophagy. We highlight examples of splicing resolution and increased protein levels following snaR-A depletion for a wide-ranging set of factors, suggesting snaR-A-driven splicing defects may have far-reaching effects that re-shape the cellular proteome. These findings help clarify the molecular activities and consequences of snaR-A express- ion in cancer, and altogether establish a novel mechanism through which Pol III overactivity may promote tumorigenesis.

2024-07-24 | GSE271057 | GEO

CHERP controls alternative mRNA splicing in human cell line

Project description:Calcium Homeostasis Endoplasmic Reticulum Protein (CHERP) is co-localized with inositol 1,4,5-trisphosphate receptor (IP3R) in the endoplasmic reticulum or peri-nuclear part, and has been considered to have a role in intracellular calcium signaling. Recently, it has recognized that CHERP structurally carries nuclear localization signal and arginine/serine-dipeptide repeats like domain, and interacts with spliceosome. In this study, we showed that poly (A)+ RNA was accumulated in the nucleus on CHERP depletion. Using the global analysis, CHERP regulated alternative mRNA splicing events through the interaction with U2 snRNP and U2 snRNP related proteins. Our analysis indicated that intron retention was most frequently observed among five alternative splicing patterns in accordance with the accumulation of poly (A)+ RNA in the nucleus. Further, intron retention and cassette exon choice were influenced by the strength of 5’ or 3’ splice site, GC content, or intron length. In addition, CHERP depletion induced the abnormality of cell cycle progression at M phase and cell division. These results suggested that CHERP was involved in the regulation of alternative splicing.

2022-06-19 | GSE193399 | GEO

Genome-wide analysis of gene expression and intron retention during development in a U12-type splicing-deficient zebrafish mutant [RNA-seq]

Project description:To determine the global impact of the clbn mutation on gene expression and efficiency of U2- and U12-type splicing, we analyzed the transcriptome of 108hpf wt and clbn mutant larvae by microarrays and RNA sequencing. RNAseq data was used to characterize intron retention of U2-type and U12-type intron on a genome-wide scale to confirm that rnpc3 deficiency specifically impairs U12-type splicing. RNAseq and microarray data were combined to yield high-confidence lists of differentially expressed genes which show that impaired U12-type splicing has a wide-ranging effect on the developing transcriptome. RNAseq libraries prepared from 108 hours post-fertilization zebrafish larvae (approx. 60 embryos each, genotyped homozygous wildtype and homozygous clbns841 mutants, respectively)

2014-02-05 | E-GEOD-53758 | biostudies-arrayexpress

Genome-wide analysis of gene expression and intron retention during deveopment in a U12-type splicing-deficient zebrafish mutant [microarray]

Project description:To determine the global impact of the clbn mutation on gene expression and efficiency of U2- and U12-type splicing, we analyzed the transcriptome of 108hpf wt and clbn mutant larvae by microarrays and RNA sequencing. RNAseq data was used to characterize intron retention of U2-type and U12-type intron on a genome-wide scale to confirm that rnpc3 deficiency specifically impairs U12-type splicing. RNAseq and microarray data were combined to yield high-confidence lists of differentially expressed genes which show that impaired U12-type splicing has a wide-ranging effect on the developing transcriptome. Total RNA was prepared from pools consisting of approx. 20 individually genotyped homozygous wildtype or mutant larvae, respectively. Three biologically independent replicate pools were generated and analyzed for each condition.

2014-02-05 | E-GEOD-53934 | biostudies-arrayexpress

PP2A inhibition instructs spliceosome phosphorylation patterns to create splicing vulnerability in colon adenocarcinoma

Project description:Protein phosphatase 2A (PP2A) is a promiscuous enzyme that acts on many aspects of cellular physiology. It remains unclear however, which of the cellular processes are most perturbed upon inhibition of PP2A and how such perturbations could be exploited therapeutically. Here, we report an unanticipated sensitivity of the splicing machinery to phosphorylation changes in response to phosphatase 2A (PP2A) inhibition by LB-100 in colorectal adenocarcinoma. We observe enrichment for differentially phosphorylated sites within cancer-critical splicing nodes of U2 snRNP, SRSF and hnRNP proteins. These phosphorylation changes endow LB-100 treated colorectal adenocarcinoma cells with differential splicing patterns. Over 1000 exon skipping and intron retention events were enriched in PP2A-inhibited cells affecting the splicing of regulators of genomic integrity and DNA damage response. Finally, alternatively spliced transcripts downstream to LB-100 are predicted to be a source of neoantigens that can improve cancer treatment outcomes in response to immune checkpoint modulators. Collectively, our findings provide a potential explanation for the pre-clinical and clinical observations that inhibition of PP2A results in increased sensitivity of cancer cells to immune checkpoint blockade and DNA damaging agents.

2024-06-16 | PXD043658 | Pride

PP2A inhibition instructs spliceosome phosphorylation patterns to create splicing vulnerability in colon adenocarcinoma

Project description:Protein phosphatase 2A (PP2A) is a promiscuous enzyme affecting cellular physiology. It is unclear however, which of the cellular processes are most perturbed upon PP2A inhibition and how such perturbations could be exploited therapeutically. Here, we report an unanticipated sensitivity of the splicing machinery to phosphorylation changes in response to PP2A inhibition by LB-100 in colorectal adenocarcinoma. We observe enrichment for differentially phosphorylated sites within cancer-critical splicing nodes of U2 snRNP, SRSF and hnRNP proteins. Changed phosphorylation endows LB-100 treated colorectal adenocarcinoma cells with differential splicing patterns. Over 1000 exon skipping and intron retention events in PP2A-inhibited cells affect predominantly regulators of genomic integrity. Finally, LB-100-evoked alternative splicing is predicted to be a source of neoantigens that can improve cancer treatment responses to immune modulators. Our findings provide a potential explanation for the pre-clinical and clinical observations that PP2A inhibition sensitizes cancer cells to immune checkpoint blockade and genotoxic agents.

2024-04-11 | GSE236625 | GEO

Genome-wide analysis of gene expression and intron retention during deveopment in a U12-type splicing-deficient zebrafish mutant [microarray]

2014-02-05 | GSE53934 | GEO

Genome-wide analysis of gene expression and intron retention during development in a U12-type splicing-deficient zebrafish mutant [RNA-seq]

2014-02-05 | GSE53758 | GEO

CDK11 phosphorylates SF3B1 and is essential for constitutive splicing (ChIP-seq)

Project description:Pre-mRNA splicing is a highly regulated process catalyzing intron excision by spliceosome. Spliceosome activation is a major control step requiring dramatic protein and RNA rearrangements leading to a catalytically active complex. Prior research has linked hyperphosphorylation of SF3B1, a subunit of U2 snRNP, with spliceosome activation and catalytically active spliceosome, rendering a relevant kinase a key player for pre-mRNA splicing. Here we use OTS964, the first potent inhibitor of cyclin-dependent kinase 11 (CDK11), to show rapid and selective dephosphorylation of SF3B1 on threonines required for spliceosome activation. CDK11 associates with SF3B1 and its inhibition causes massive intron retention, block in precatalytic spliceosome complex B to activated spliceosome complex Bact transition and accumulation of non-functional spliceosomes on pre-mRNA and chromatin. These studies reveal crucial regulatory role of CDK11 in human pre-mRNA splicing and define the compound OTS964 as a quality chemical biology probe for CDK11.

2022-07-09 | GSE185812 | GEO

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