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Cancer associated SF3B1 hotspot mutations induce cryptic 3' splice site selection through use of a different branch point

ABSTRACT: 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.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE72790 | GEO | 2015/09/08

SECONDARY ACCESSION(S): PRJNA295064

REPOSITORIES: GEO

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Cancer associated SF3B1 hotspot mutations induce cryptic 3' splice site selection through use of a different branch point

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

Novel SF3B1 Deletion Mutations Result in Aberrant RNA Splicing in CLL Patients

Project description:Recurrent mutations in RNA splicing factors SF3B1, U2AF1, and SRSF2 have been reported in hematologic cancers including myelodysplastic syndromes (MDS) and chronic lymphocytic leukemia (CLL). However, SF3B1 is the only splicing associated gene to be found mutated in CLL and has been shown to induce aberrant splicing. To investigate if any other genomic aberration caused similar transcriptome changes, we clustered RNASeq samples based on an alternative 3’ splice site (ss) pattern previously identified in SF3B1-mutant CLL patients. Out of 215 samples, we identified 37 (17%) with alternative 3’ ss usage, the majority of which harbored known SF3B1 hotspot mutations. Interestingly, 3 patient samples carried previously unreported in-frame deletions in SF3B1 around K700, the most frequent mutation hotspot. To study the functional effects of these deletions, we used various minigenes demonstrating that recognition of canonical 3’ ss and alternative branchsite are required for aberrant splicing, as observed for SF3B1 p.K700E. The common mechanism of action of these deletions and substitutions result in similar sensitivity of primary cells towards splicing inhibitor E7107. Altogether, these data demonstrate that novel SF3B1 in-frame deletion events identified in CLL result in aberrant splicing, a common biomarker in spliceosome-mutant cancers.

2017-06-27 | GSE95352 | GEO

Transcriptomic Characterization of PRP5 knockdown in HEK293T cells

Project description:Splicing abnormality has been observed in various types of SF3B1-mutated tumors. Aberrant usage of 3’SS has been established as the most frequent splicing defect and is attributed to altered BS selection. In this study, we examined whether reduced PRP5 expression would phenocopy the splicing defects of SF3B1 cancer mutations.

2022-10-01 | GSE185713 | GEO

Identification of New Branch Points and Unconventional Introns in Saccharomyces cerevisiae

Project description:Spliced messages constitute one-fourth of expressed mRNAs in the yeast Saccharomyces cerevisiae, and most mRNAs in metazoans. Splicing requires 5' splice site (5'SS), branch point (BP), and 3' splice site (3'SS) elements, but the role of the BP in splicing control is poorly understood because BP identification remains difficult. We developed a high-throughput method, Branch-seq, to map BP and 5'SS of isolated RNA lariats. Applied to S. cerevisiae, Branch-seq detected 76% of expressed, annotated BPs and identified a comparable number of novel BPs. We used RNA-seq to confirm associated 3'SS locations, identifying some 200 novel splice junctions, including an AT-AC intron. We show that several yeast introns use two or even three different BPs, with effects on 3'SS choice, protein coding potential, or RNA stability and identify novel introns whose splicing changes during meiosis or in response to stress. Together, these findings reveal BP-based regulation and demonstrate unanticipated complexity of splicing in yeast.

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Identification of New Branch Points and Unconventional Introns in Saccharomyces cerevisiae

2016-08-01 | E-GEOD-68022 | biostudies-arrayexpress

Two oppositely-chargedsf3b1 mutations cause defective development, impaired immune response, and aberrant selection of intronic branch sites in Drosophila

Project description:Somatic SF3b1 mutations occur in many cancers, and the highly conserved H662 residue is one of the most frequently mutated sites. To address their mechanism on splicing alteration and effects on development, we constructed mutant strains at the corresponding residue H698 in Drosophila using CRISPR-Cas9 system. Two mutations, H698D and H698R, were selected due to their presence in patients and the significantly opposite charges. Both the sf3b1-H698D and –H698R mutant flies exhibit developmental defects including less egg-laying, decreased hatching rates, delayed morphogenesis and shorter lifespan. Interestingly, the H698D mutant has decreased resistance to fungi infection, while the H698R mutant has impaired climbing ability. Further RNA-seq data finds altered expression of immunity response genes and changed alternative splicing of muscle and neural-related genes in the two mutants respectively. Lariat sequencing reveal that the sf3b1-H662 mutations cause aberrant selection of multiple intronic branch sites and the H698R mutant prefers to use upstream branch sites in the alternative splicing changed events. This study provides in vivo evidence from Drosophila to elucidate how the highly conserved SF3b1 cancer mutations alter splicing and their consequences in the development and immune systems.

2021-10-08 | GSE171002 | GEO

RNAseq of 76 samples from Uveal Melanoma tumors

Project description:Hotspot mutations in the spliceosome gene SF3B1 are reported in 20% of uveal melanomas. SF3B1 is involved in 3'-splice site (3'ss) recognition during RNA splicing; however, the molecular mechanisms of its mutation have remained unclear. Here we show, using RNA-Seq analyses of uveal melanoma, that the SF3B1 R625/K666 mutation results in deregulated splicing at a subset of junctions, mostly by the use of alternative 3'ss

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b4290dba-60d5-4af4-a857-5c0419dff5de - samples

| EGAD00001004398 | EGA

The impact of Prp18p on splicing fidelity and efficiency in budding yeast

Project description:Fidelity of 3´-splice site (3´SS) selection by the spliceosome is critical for proper gene expression but is a daunting task considering the low complexity of the 3´SS consensus YAG. Here we show that loss of the splicing factor Prp18p in budding yeast activates a diverse array of alternative 3´SS at more than half of all introns. Some alternative sites highly diverge from the YAG consensus, demonstrating a critical role for Prp18p in promoting spliceosome fidelity. Usage of alternative 3´SS is determined by distance from the branchpoint, local RNA secondary structures, upstream poly(U) content, and adenosine enrichment in exons. The 3´SS fidelity function of Prp18p can be genetically uncoupled from its role in splicing efficiency and is promoted by interactions with Slu7p and Prp8p. Taken together, these results provide a comprehensive mechanism into how the spliceosome achieves specificity of 3´SS selection and how it prevents aberrant activation of non-canonical splice sites.

2020-05-25 | GSE131797 | GEO

Mutations in splicing factor SF3B1 promote transformation through MYC stabilization

Project description:Although mutations in the RNA splicing factor SF3B1 are frequently observed in multiple human cancers, their functional role in promoting tumorigenesis and therapeutic significance remain poorly understood. Here we characterize the splicing landscape of 79 tumors and 12 isogenic cell lines harboring SF3B1 hotspot mutations, identifying hundreds of cryptic 3’ splice site (ss) events shared as well as specific to different tumor types. Regulatory network analysis shows that tumors harboring the most common hotspot mutation in SF3B1 (SF3B1K700E) activate the MYC transcriptional program. SF3B1 mutations lead to a dramatic decay of transcripts encoding the key PP2A phosphatase subunit PPP2R5A due to aberrant 3’ss usage, resulting in increased c-MYC serine 62 phosphorylation (allowing MYC to escape ubiquitin-mediated degradation) and in increased BCL2 serine 70 phosphorylation (leading to anti-apoptotic effects). This effect of SF3B1K700E on c-MYC and BCL2 activation through post-translational regulation was conserved across human and mouse cells and could be rescued by restored expression of PPP2R5A. Consonant with this, mutant SF3B1 promoted c-MYC driven tumorigenesis could be restored by the PP2A activating agent FTY-720. This study reveals the functional contribution of mutant SF3B1 to tumorigenesis through regulation of established oncogenic pathways and provides therapeutic strategies for related tumors.

2020-05-01 | GSE116391 | GEO

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