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

Jure Borišek, Andrea Saltalamacchia, Anna Gallì, Giulia Palermo, Elisabetta Molteni, Luca Malcovati, Alessandra Magistrato

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
JournalBiomolecules
Volume9
Issue number10
DOIs
Publication statusPublished - Oct 21 2019

Fingerprint

Spliceosomes
RNA Splice Sites
RNA Precursors
RNA Splicing
Atoms
Site selection
Mutation
Alternative Splicing
Hematologic Neoplasms
Molecular Dynamics Simulation
Point Mutation
Gene expression
Yeast
Introns
Molecular dynamics
Protein Isoforms
Genes
Yeasts
Gene Expression
Messenger RNA

Keywords

  • molecular dynamics
  • RNA
  • spliceosome
  • splicing

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

Cite this

Disclosing the Impact of Carcinogenic SF3b Mutations on Pre-mRNA Recognition Via All-Atom Simulations. / Borišek, Jure; Saltalamacchia, Andrea; Gallì, Anna; Palermo, Giulia; Molteni, Elisabetta; Malcovati, Luca; Magistrato, Alessandra.

In: Biomolecules, Vol. 9, No. 10, 21.10.2019.

Research output: Contribution to journalArticle

Borišek, J, Saltalamacchia, A, Gallì, A, Palermo, G, Molteni, E, Malcovati, L & Magistrato, A 2019, 'Disclosing the Impact of Carcinogenic SF3b Mutations on Pre-mRNA Recognition Via All-Atom Simulations', Biomolecules, vol. 9, no. 10. https://doi.org/10.3390/biom9100633
Borišek, Jure ; Saltalamacchia, Andrea ; Gallì, Anna ; Palermo, Giulia ; Molteni, Elisabetta ; Malcovati, Luca ; Magistrato, Alessandra. / Disclosing the Impact of Carcinogenic SF3b Mutations on Pre-mRNA Recognition Via All-Atom Simulations. In: Biomolecules. 2019 ; Vol. 9, No. 10.
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