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The SF3b Complex is an Integral Component of the Spliceosome and Targeted by Natural Product-Based Inhibitors

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Macromolecular Protein Complexes III: Structure and Function

Part of the book series: Subcellular Biochemistry ((SCBI,volume 96))

Abstract

In this chapter, the essential role of the SF3b multi-protein complex will be discussed in the context of the overall spliceosome. SF3b is critical during spliceosome assembly for recognition of the branch point (BP) adenosine and, by de facto, selection of the 3′ splice site. This complex is highly dynamic, undergoing significant conformational changes upon loading of the branch duplex RNA and in its relative positioning during spliceosomal remodeling from the A, pre-B, B, Bact and B* complexes. Ultimately, during the spliceosome activation phase, SF3b must be displaced to unmask the branch point adenosine for the first splicing reaction to occur. In certain cancers, such as the hematological malignancies CML, CLL and MDS, the SF3b subunit SF3B1 is frequently mutated. Recent studies suggest these mutations lead to inappropriate branch point selection and mis-splicing events that appear to be drivers of disease. Finally, the SF3b complex is the target for at least three different classes of natural product-based inhibitors. These inhibitors bind in the BP adenosine-binding pocket and demonstrate a pre-mRNA competitive mechanism of action resulting in either intron retention or exon skipping. These compounds are extremely useful as chemical probes to isolate and characterize early stages of spliceosome assembly. They are also being explored preclinically and clinically as possible agents for hematological cancers.

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Abbreviations

BP:

Branch point

BPRS:

Branch point recognition sequence

BS:

Branch sequence

BSL:

Branch stem loop

CMML:

Chronic myelomonocytic leukemia

CLL:

Chronic lymphocytic leukemia

EM:

Electron microscopy

ILS:

Intron lariat spliceosome

ISL:

Internal stem loop

MDS:

Myelodysplastic syndromes

mRNA:

Messenger RNA

NMD:

Nonsense-mediated decay

NMR:

Nuclear magnetic resonance

NTC:

Nineteen complex

NTR:

Nineteen related

Plad:

Pladienolide

PY:

Polypyrimidine

RNA:

Ribonucleic acid

RRM:

RNA recognition motif

SF:

Splicing factor

snRNP:

Small nuclear ribonucleoproteins

snRNA:

Small nuclear RNAs

SS:

Splice site

ULM:

U2AF ligand motifs

UHM:

U2AF homology motif

U2AF:

U2 auxiliary factor

WT:

Wild type

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  1. H3 Biomedicine, Inc., Cambridge, MA, 02139, USA

    Nicholas A. Larsen

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Correspondence to Nicholas A. Larsen .

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Editors and Affiliations

  1. Institute of Molecular Physiology, University of Mainz, Mainz, Rheinland-Pfalz, Germany

    J. Robin Harris

  2. School of Natural and Environmental Sciences, Newcastle University, Newcastle upon Tyne, UK

    Jon Marles-Wright

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Larsen, N.A. (2021). The SF3b Complex is an Integral Component of the Spliceosome and Targeted by Natural Product-Based Inhibitors. In: Harris, J.R., Marles-Wright, J. (eds) Macromolecular Protein Complexes III: Structure and Function. Subcellular Biochemistry, vol 96. Springer, Cham. https://doi.org/10.1007/978-3-030-58971-4_12

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