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

Samar Alsafadi, Alexandre Houy, Aude Battistella, Tatiana Popova, Michel Wassef, Emilie Henry, Franck Tirode, Angelos Constantinou, Sophie Piperno-Neumann, Sergio Roman-Roman, Martin Dutertre and Marc-Henri Stern ()
Additional contact information
Samar Alsafadi: INSERM U830, Institut Curie, PSL Research University
Alexandre Houy: INSERM U830, Institut Curie, PSL Research University
Aude Battistella: INSERM U830, Institut Curie, PSL Research University
Tatiana Popova: INSERM U830, Institut Curie, PSL Research University
Michel Wassef: Depatment of Developmental Biology and Genetics, CNRS UMR 3215/INSERM U934, Institut Curie, PSL Research University
Emilie Henry: Institut Curie, PSL Research University
Franck Tirode: INSERM U830, Institut Curie, PSL Research University
Angelos Constantinou: CNRS UPR 1142, IGH-Institute of Human Genetics
Sophie Piperno-Neumann: Institut Curie
Sergio Roman-Roman: Institut Curie, PSL Research University
Martin Dutertre: CNRS UMR 3348, Institut Curie, PSL Research University
Marc-Henri Stern: INSERM U830, Institut Curie, PSL Research University

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: Abstract 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 SF3B1R625/K666 mutation results in deregulated splicing at a subset of junctions, mostly by the use of alternative 3′ss. Modelling the differential junctions in SF3B1WT and SF3B1R625/K666 cell lines demonstrates that the deregulated splice pattern strictly depends on SF3B1 status and on the 3’ss-sequence context. SF3B1WT knockdown or overexpression do not reproduce the SF3B1R625/K666 splice pattern, qualifying SF3B1R625/K666 as change-of-function mutants. Mutagenesis of predicted branchpoints reveals that the SF3B1R625/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.

Date: 2016
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DOI: 10.1038/ncomms10615

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