Functional and conformational impact of cancer-associated SF3B1 mutations depends on the position and the charge of amino acid substitution

Christine Canbezdi; Malcy Tarin; Alexandre Houy; Dorine Bellanger; Tatiana Popova; Marc-Henri Stern; Sergio Roman-Roman; Samar Alsafadi

doi:10.1016/j.csbj.2021.02.012

Functional and conformational impact of cancer-associated SF3B1 mutations depends on the position and the charge of amino acid substitution

Comput Struct Biotechnol J. 2021 Feb 27:19:1361-1370. doi: 10.1016/j.csbj.2021.02.012. eCollection 2021.

Authors

Christine Canbezdi¹, Malcy Tarin¹, Alexandre Houy², Dorine Bellanger^{2

3}, Tatiana Popova², Marc-Henri Stern², Sergio Roman-Roman¹, Samar Alsafadi¹

Affiliations

¹ Institut Curie, PSL Research University, Uveal Melanoma Group, Translational Research Department, Paris, France.
² Institut Curie, PSL Research University, INSERM U830, DNA Repair and Uveal Melanoma (D.R.U.M.), Paris, France.
³ University of Tours, INSERM UMR1069, Tours, France.

Abstract

The hotspot mutations of SF3B1, the most frequently mutated splicing gene in cancers, contribute to oncogenesis by corrupting the mRNA splicing. Further SF3B1 mutations have been reported in cancers but their consequences remain unclear. Here, we screened for SF3B1 mutations in the vicinity of the hotspot region in tumors. We then performed in-silico prediction of the functional outcome followed by in-cellulo modelling of different SF3B1 mutants. We show that cancer-associated SF3B1 mutations present varying functional consequences that are loosely predicted by the in-silico algorithms. Analysis of the tertiary structure of SF3B1 mutants revealed that the resulting splicing errors may be due to a conformational change in SF3B1 N-terminal region, which mediates binding with other splicing factors. Our study demonstrates a varying functional impact of SF3B1 mutations according to the mutated codon and the amino acid substitution, implying unequal pathogenic and prognostic potentials of SF3B1 mutations in cancers.

Keywords: Cancer; Functional impact; In-silico analysis; Missense mutations; Protein conformation; SF3B1; Splicing.