The biological function and clinical significance of SF3B1 mutations in cancer

Abstract

Spliceosome mutations have become the most interesting mutations detected in human cancer in recent years. The spliceosome, a large, dynamic multimegadalton small nuclear ribonucleoprotein composed of small nuclear RNAs associated with proteins, is responsible for removing introns from precursor mRNA (premRNA) and generating mature, spliced mRNAs. SF3B1 is the largest subunit of the spliceosome factor 3b (SF3B) complex, which is a core component of spliceosomes. Recurrent somatic mutations in SF3B1 have been detected in human cancers, including hematological malignancies and solid tumors, and indicated to be related to patient prognosis. This review summarizes the research progress of SF3B1 mutations in cancer, including SF3B1 mutations in the HEAT domain, the multiple roles and aberrant splicing events of SF3B1 mutations in the pathogenesis of tumors, and changes in mutated cancer cells regarding sensitivity to SF3B small-molecule inhibitors. In addition, the potential of SF3B1 or its mutations to serve as biomarkers or therapeutic targets in cancer is discussed. The accumulated knowledge about SF3B1 mutations in cancer provides critical insight into the integral role the SF3B1 protein plays in mRNA splicing and suggests new targets for anticancer therapy.

Keywords: Cancer; Mutation; RNA splicing; SF3B1.

Fig. 1

SF3B1 functions in the stepwise assembly of the U2- and U12-dependent spliceosomes. There are two types of spliceosomes: U2-dependent spliceosomes (left) and U12-dependent spliceosomes (right). Assembly of the U2-dependent spliceosome consists of 5 snRNPs, U1, U2, U5, and U4/U6 snRNPs; the U12-dependent spliceosome also consists of 5 snRNPs: U11, U12, U5, and U4atac/U6atac snRNPs. The difference between the two spliceosomes is in the consensus splice-site sequences, namely, U2-type or U12-type premRNA introns. SF3B1 is shared in the core components between the two spliceosomes and plays a key role in the recognition and selection of the branch site (BS) by interacting with premRNA in a sequence-independent manner, reinforcing stability during U2 (or U12) snRNA/BS interaction

Fig. 2

Distribution of mutations in SF3B1. More than 80 mutated codons have been found in the HEAT domain of the SF3B1 gene, especially H4-H12

Fig. 3

A model for aberrant 3′ ss selection induced by SF3B1 mutations. a: Schematic representation of SF3B1WT-mediated splicing, generating canonical transcript and producing canonical protein. b: Schematic representation of SF3B1MUT-mediated splicing, leading to the binding of U2 snRNP and alternative branchpoint sequence (BPSʹ) or usage of a cryptic 3′ splice and resulting in aberrant/alternative transcript with aberrant/alternative protein as well as increased nonsense-mediated decay (MMD)

Fig. 4

Venn diagrams showing SF3B1 mutation-associated aberrant splicing genes identified by RNAseq and validated by qRT-PCR in CLL, MDS, UM, and BC. At least 46 genes are produced by aberrant splicing events in SF3B1^mut CLL, MDS, UM, and BC. Among them, BRD9 is shared by CLL, MDS and UM and TMEM14C by MDS, UM and BC. SEPT6 and SEPT2 are shared by CLL and MDS, ENOSF1 by MDS and UM, and DYNLL1 by MDS and BC

Fig. 5

Molecular effects of SF3B small-molecule inhibitors on 3ʹ splice site recognition mediated by SF3B1 mutation. a: Normal condition of 3ʹ splice site recognition induced by SF3B1WT. b: Effects of inhibitors on 3ʹ splice site recognition induced by SF3B1WT. PlaB inhibits mRNA splicing by fitting into a space between SF3B1 and SF3B3; E7101 and SSA inhibit splicing by fitting into SF3B1. c: Effects of inhibitors on 3ʹ splice site recognition induced by SF3B1MUT. Mutations impair the binding of PlaB, E7101 or SSA to SF3B1