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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. 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.

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