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

Biomolecules

Alessandra Magistrato¹  Jure Borišek¹  Giulia Palermo²  Luca Malcovati³  Anna Gallì³  Elisabetta Molteni⁴  Andrea Saltalamacchia⁵ 

[1] CNR-IOM-Democritos National Simulation Center c/o SISSA, 34136 Trieste, Italy;Department of Bioengineering, University of California Riverside, Riverside, CA 92521, USA;Department of Hematology, IRCCS S. Matteo Hospital Foundation, 27100 Pavia, Italy;Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy;International School for Advanced Studies (SISSA), 34136 Trieste, Italy;

关键词: rna;    molecular dynamics;    spliceosome;    splicing;   

DOI  :  10.3390/biom9100633

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown