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Disclosing the Impact of Carcinogenic SF3b Mutations on Pre-mRNA Recognition Via All-Atom Simulations

CNR-IOM-Democritos National Simulation Center c/o SISSA, 34136 Trieste, Italy
National Institute of Chemistry, 1000 Ljubljana, Slovenia
International School for Advanced Studies (SISSA), 34136 Trieste, Italy
Department of Hematology, IRCCS S. Matteo Hospital Foundation, 27100 Pavia, Italy
Department of Bioengineering, University of California Riverside, Riverside, CA 92521, USA
Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
Author to whom correspondence should be addressed.
Biomolecules 2019, 9(10), 633;
Received: 21 August 2019 / Revised: 15 October 2019 / Accepted: 17 October 2019 / Published: 21 October 2019
(This article belongs to the Section Biomacromolecules)
The spliceosome accurately promotes precursor messenger-RNA splicing by recognizing specific noncoding intronic tracts including the branch point sequence (BPS) and the 3’-splice-site (3’SS). Mutations of Hsh155 (yeast)/SF3B1 (human), which is a protein of the SF3b factor involved in BPS recognition and induces altered BPS binding and 3’SS selection, lead to mis-spliced mRNA transcripts. Although these mutations recur in hematologic malignancies, the mechanism by which they change gene expression remains unclear. In this study, multi-microsecond-long molecular-dynamics simulations of eighth distinct ∼700,000 atom models of the spliceosome Bact complex, and gene sequencing of SF3B1, disclose that these carcinogenic isoforms destabilize intron binding and/or affect the functional dynamics of Hsh155/SF3B1 only when binding non-consensus BPSs, as opposed to the non-pathogenic variants newly annotated here. This pinpoints a cross-talk between the distal Hsh155 mutation and BPS recognition sites. Our outcomes unprecedentedly contribute to elucidating the principles of pre-mRNA recognition, which provides critical insights on the mechanism underlying constitutive/alternative/aberrant splicing. View Full-Text
Keywords: RNA; molecular dynamics; spliceosome; splicing RNA; molecular dynamics; spliceosome; splicing
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Borišek, J.; Saltalamacchia, A.; Gallì, A.; Palermo, G.; Molteni, E.; Malcovati, L.; Magistrato, A. Disclosing the Impact of Carcinogenic SF3b Mutations on Pre-mRNA Recognition Via All-Atom Simulations. Biomolecules 2019, 9, 633.

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