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Open AccessArticle

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

1
CNR-IOM-Democritos National Simulation Center c/o SISSA, 34136 Trieste, Italy
2
National Institute of Chemistry, 1000 Ljubljana, Slovenia
3
International School for Advanced Studies (SISSA), 34136 Trieste, Italy
4
Department of Hematology, IRCCS S. Matteo Hospital Foundation, 27100 Pavia, Italy
5
Department of Bioengineering, University of California Riverside, Riverside, CA 92521, USA
6
Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
*
Author to whom correspondence should be addressed.
Biomolecules 2019, 9(10), 633; https://doi.org/10.3390/biom9100633
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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