Structures of SF3b1 Reveal a Dynamic Achilles Heel of Spliceosome Assembly: Implications for Cancer-associated Abnormalities and Drug Discovery

Overview

Journal Biochim Biophys Acta Gene Regul Mech

Publisher Elsevier

Specialties Biochemistry
Biophysics
Genetics
Molecular Biology

Date 2019 Nov 11

PMID 31707043

Citations 15

Authors

Debanjana Maji

Alan Grossfield

Clara L Kielkopf

Affiliations

Soon will be listed here.

Abstract

The pre-mRNA splicing factor SF3b1 exhibits recurrent mutations among hematologic malignancies and cancers, and consequently is a major therapeutic target of clinically-advanced spliceosome inhibitors. In this review, we highlight and rigorously analyze emerging views of SF3b1 conformational transitions, including the human SF3b particle either in isolation or bound to spliceosome inhibitors, and human or yeast spliceosome assemblies. Among spliceosome states characterized to date, an SF3b1 α-helical superhelix significantly closes to surround a U2 small nuclear RNA duplex with the pre-mRNA branch point sequence. The SF3b1 torus is locally unwound at an active site adenosine, whereas protein cofactors appear to stabilize overall closure in the spliceosome. Network analyses demonstrates that the natural SF3b1 dynamics mimic its conformational change in the spliceosome, raising the possibility of conformational selection underpinning spliceosome assembly. These dynamic SF3b1 conformations have consequences for gatekeeping of spliceosome assembly and therapeutic targeting of its cancer-associated dysfunction.

Citing Articles

SF3B1 thermostability as an assay for splicing inhibitor interactions.

Amorello A, Chandrashekar Reddy G, Melillo B, Cravatt B, Ghosh A, Jurica M J Biol Chem. 2024; 301(2):108135.

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Structural screening and molecular simulation identify potential ligands against the K700E hot spot variant and functional pockets of SF3B1 to modulate splicing in myelodysplastic syndrome.

Garcia R, Atis M, Cox A, Koduru P Heliyon. 2024; 10(12):e32729.

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Biological relevance of alternative splicing in hematologic malignancies.

Szelest M, Giannopoulos K Mol Med. 2024; 30(1):62.

PMID: 38760666 PMC: 11100220. DOI: 10.1186/s10020-024-00839-2.

Small molecules modulating RNA splicing: a review of targets and future perspectives.

Bouton L, Ecoutin A, Malard F, Campagne S RSC Med Chem. 2024; 15(4):1109-1126.

PMID: 38665842 PMC: 11042171. DOI: 10.1039/d3md00685a.

Variations of intronic branchpoint motif: identification and functional implications in splicing and disease.

Xie J, Wang L, Lin R Commun Biol. 2023; 6(1):1142.

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