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

Biomolecules. 2019 Oct 21;9(10):633. doi: 10.3390/biom9100633.


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.

Keywords: RNA; molecular dynamics; spliceosome; splicing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinogens / chemistry*
  • Humans
  • Molecular Dynamics Simulation*
  • Mutation*
  • Phosphoproteins / chemistry*
  • Phosphoproteins / genetics*
  • Principal Component Analysis
  • RNA Precursors / chemistry*
  • RNA Precursors / genetics
  • RNA Splicing / genetics
  • RNA Splicing Factors / chemistry*
  • RNA Splicing Factors / genetics*
  • Ribonucleoprotein, U2 Small Nuclear / chemistry*
  • Ribonucleoprotein, U2 Small Nuclear / genetics*
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae Proteins / chemistry*
  • Saccharomyces cerevisiae Proteins / genetics*
  • Static Electricity


  • Carcinogens
  • HSH155 protein, S cerevisiae
  • Phosphoproteins
  • RNA Precursors
  • RNA Splicing Factors
  • Ribonucleoprotein, U2 Small Nuclear
  • SF3B1 protein, human
  • Saccharomyces cerevisiae Proteins