Misregulation of Pre-mRNA Alternative Splicing in Cancer

Zhang, Jian; Manley, James L.

doi:10.1158/2159-8290.cd-13-0253

Cited by 273 publications

(243 citation statements)

References 99 publications

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“…The accumulation of disease-related mutations in the spliceosome, the machinery for intron recognition and removal, correlates with aberrations in alternative splicing that have been suggested to contribute to tumorigenesis (Tazi et al 2009;Zhang and Manley 2013;Sveen et al 2016). Disease-related mutations cluster in proteins involved in spliceosome assembly, particularly ones important for intron recognition, such as SF3B1 (also known as SAP155, SF3b155, and Hsh155p), SRSF1, and U2AF (Yoshida et al 2011;Quesada et al 2012).…”

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SF3B1/Hsh155 HEAT motif mutations affect interaction with the spliceosomal ATPase Prp5, resulting in altered branch site selectivity in pre-mRNA splicing

et al. 2016

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Mutations in the U2 snRNP component SF3B1 are prominent in myelodysplastic syndromes (MDSs) and other cancers and have been shown recently to alter branch site (BS) or 3 ′ splice site selection in splicing. However, the molecular mechanism of altered splicing is not known. We show here that hsh155 mutant alleles in Saccharomyces cerevisiae, counterparts of SF3B1 mutations frequently found in cancers, specifically change splicing of suboptimal BS pre-mRNA substrates. We found that Hsh155p interacts directly with Prp5p, the first ATPase that acts during spliceosome assembly, and localized the interacting regions to HEAT (Huntingtin, EF3, PP2A, and TOR1) motifs in SF3B1 associated with disease mutations. Furthermore, we show that mutations in these motifs from both human disease and yeast genetic screens alter the physical interaction with Prp5p, alter branch region specification, and phenocopy mutations in Prp5p. These and other data demonstrate that mutations in Hsh155p and Prp5p alter splicing because they change the direct physical interaction between Hsh155p and Prp5p. This altered physical interaction results in altered loading (i.e., "fidelity") of the BS-U2 duplex into the SF3B complex during prespliceosome formation. These results provide a mechanistic framework to explain the consequences of intron recognition and splicing of SF3B1 mutations found in disease.

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SF3B1/Hsh155 HEAT motif mutations affect interaction with the spliceosomal ATPase Prp5, resulting in altered branch site selectivity in pre-mRNA splicing

et al. 2016

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“…Alterations in SF3B1 were initially discovered in myelodysplastic syndromes (MDSs) and chronic lymphocytic leukemia (CLL), together with other mutations of splicing factors, such as U2AF1, SRSF2 and ZRSR2 (refs 1-3). Importantly, these genes encode proteins that are all involved in 3 0 -splice site recognition during RNA splicing 4 . It has been shown that SF3B1 is mutated in a significant proportion (B20%) of uveal melanoma (UM), a rare malignant entity deriving from melanocytes from the uveal tract [5][6][7] , and in other solid tumours at lesser frequencies 8,9 .…”

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confidence: 99%

Cancer-associated SF3B1 mutations affect alternative splicing by promoting alternative branchpoint usage

Alsafadi¹,

Houy²,

Battistella³

et al. 2016

European Journal of Cancer

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Hotspot mutations in the spliceosome gene SF3B1 are reported in B20% of uveal melanomas. SF3B1 is involved in 3 0 -splice site (3 0 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 0 ss. Modelling the differential junctions in SF3B1 WT and SF3B1 R625/K666 cell lines demonstrates that the deregulated splice pattern strictly depends on SF3B1 status and on the 3'ss-sequence context. SF3B1 WT knockdown or overexpression do not reproduce the SF3B1 R625/K666 splice pattern, qualifying SF3B1 R625/K666 as change-of-function mutants. Mutagenesis of predicted branchpoints reveals that the SF3B1 R625/K666 -promoted splice pattern is a direct result of alternative branchpoint usage. Altogether, this study provides a better understanding of the mechanisms underlying splicing alterations induced by mutant SF3B1 in cancer, and reveals a role for alternative branchpoints in disease.

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“…Aberrant alternative splicing events are commonly observed in cancer cells and have been implicated in many types of cancer 14,15 . For example, many genes that are involved in proliferation and invasiveness are frequently alternatively spliced, and their specific splice variants, which stimulate cell proliferation and migration, and thus contribute to the transformed phenotype, are often upregulated in tumours.…”

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BCLAF1 and its splicing regulator SRSF10 regulate the tumorigenic potential of colon cancer cells

et al. 2014

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Bcl-2-associated transcription factor 1 (BCLAF1) is known to be involved in multiple biological processes. Although several splice variants of BCLAF1 have been identified, little is known about how BCLAF1 splicing is regulated or the contribution of alternative splicing to its developmental functions. Here we find that inclusion of alternative exon5a was significantly increased in colorectal cancer (CRC) samples. Knockdown of the BCLAF1 protein isoform resulting from exon5a inclusion inhibited growth and that its overexpression increased tumorigenic potential. We also found that the splicing factor SRSF10 stimulates inclusion of exon5a and has growth-inducing activity. Importantly, the upregulation of SRSF10 expression observed in clinical CRC samples parallels the increased inclusion of BCLAF1 exon5a, both of which are associated with higher tumour grade. These findings identify SRSF10 as a key regulator of BCLAF1 pre-mRNA splicing and the maintenance of oncogenic features in human colon cancer cells.

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Misregulation of Pre-mRNA Alternative Splicing in Cancer

Cited by 273 publications

References 99 publications

SF3B1/Hsh155 HEAT motif mutations affect interaction with the spliceosomal ATPase Prp5, resulting in altered branch site selectivity in pre-mRNA splicing

SF3B1/Hsh155 HEAT motif mutations affect interaction with the spliceosomal ATPase Prp5, resulting in altered branch site selectivity in pre-mRNA splicing

Cancer-associated SF3B1 mutations affect alternative splicing by promoting alternative branchpoint usage

BCLAF1 and its splicing regulator SRSF10 regulate the tumorigenic potential of colon cancer cells

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