Cancer-associated SF3B1 mutations affect alternative splicing by promoting alternative branchpoint usage
10.1038/ncomms10615
Crossref journal-article
Springer Science and Business Media LLC
Nature Communications (297)
Abstract

AbstractHotspot 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.

Bibliography

Alsafadi, S., Houy, A., Battistella, A., Popova, T., Wassef, M., Henry, E., Tirode, F., Constantinou, A., Piperno-Neumann, S., Roman-Roman, S., Dutertre, M., & Stern, M.-H. (2016). Cancer-associated SF3B1 mutations affect alternative splicing by promoting alternative branchpoint usage. Nature Communications, 7(1).

Authors 12
  1. Samar Alsafadi (first)
  2. Alexandre Houy (additional)
  3. Aude Battistella (additional)
  4. Tatiana Popova (additional)
  5. Michel Wassef (additional)
  6. Emilie Henry (additional)
  7. Franck Tirode (additional)
  8. Angelos Constantinou (additional)
  9. Sophie Piperno-Neumann (additional)
  10. Sergio Roman-Roman (additional)
  11. Martin Dutertre (additional)
  12. Marc-Henri Stern (additional)
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Dates
Type When
Created 9 years, 6 months ago (Feb. 4, 2016, 6:04 a.m.)
Deposited 2 years, 7 months ago (Jan. 4, 2023, 6:45 a.m.)
Indexed 6 days, 15 hours ago (Aug. 27, 2025, 11:50 a.m.)
Issued 9 years, 6 months ago (Feb. 4, 2016)
Published 9 years, 6 months ago (Feb. 4, 2016)
Published Online 9 years, 6 months ago (Feb. 4, 2016)
Funders 0

None

@article{Alsafadi_2016, title={Cancer-associated SF3B1 mutations affect alternative splicing by promoting alternative branchpoint usage}, volume={7}, ISSN={2041-1723}, url={http://dx.doi.org/10.1038/ncomms10615}, DOI={10.1038/ncomms10615}, number={1}, journal={Nature Communications}, publisher={Springer Science and Business Media LLC}, author={Alsafadi, Samar and Houy, Alexandre and Battistella, Aude and Popova, Tatiana and Wassef, Michel and Henry, Emilie and Tirode, Franck and Constantinou, Angelos and Piperno-Neumann, Sophie and Roman-Roman, Sergio and Dutertre, Martin and Stern, Marc-Henri}, year={2016}, month=feb }