| SF3B3, also known as SAP130, is a core subunit of the splicing factor 3b (SF3B) complex within the 17S U2 snRNP, where it contributes structurally and functionally to branch-point recognition during pre‑mRNA splicing and also participates in chromatin-associated transcriptional coactivator complexes such as STAGA and TFTC. The protein is part of the SF3B subcomplex that binds pre‑mRNA upstream of the intron branch site in a sequence-independent manner and anchors U2 snRNP to the pre‑mRNA, helping form the spliceosomal A complex and promoting selection of the branch-site adenosine that serves as the nucleophile for the first transesterification reaction. SF3B3 supports assembly and stabilization of both major (U2-type) and minor (U12-type) spliceosomes by cooperating with SF3B1 and SF3A subunits to organize the RNA–protein interface around the branch-point region, and structural work on SF3B complexes indicates a conserved mechanism of RNA recognition in which SF3B3 contributes to the scaffold that positions SF3B1’s HEAT repeats and other elements over intronic secondary structures that conceal or present branch sites. SF3B3 modulates alternative splicing of specific regulatory transcripts: in colorectal cancer, SF3B3-regulated alternative splicing of mTOR pre‑mRNA changes mTOR isoform production and promotes tumor progression by enhancing oncogenic mTOR signaling, linking SF3B3 activity directly to a major growth and survival pathway. SF3B3 also engages in noncanonical nuclear complexes, having been identified in STAGA and TFTC histone acetyltransferase assemblies that function in chromatin modification and transcriptional coactivation, indicating that SF3B3 can couple transcription and splicing within integrated gene-expression modules and potentially participate in DNA repair-associated transcriptional responses. In CD4⁺ T helper cells, nuclear Argonaute 3 forms a complex with SF3B3 to control precursor mRNA splicing and restrain type 2 immunity, with AGO3–SF3B3-dependent regulation of Nisch isoform ratios altering inflammatory responses, which expands SF3B3’s functional scope to immune pathway tuning via splicing control of signaling genes. SF3B3 expression rather than mutation appears most relevant: in estrogen receptor–positive breast cancer, high SF3B3 levels correlate with poor prognosis and endocrine resistance, and SF3B3-driven splicing changes, including altered EZH2 pre‑mRNA splicing, have been implicated in enhancing tumorigenic potential and therapy escape. De novo SF3B3 variants have been described in a novel spliceosomopathy, supporting a role for SF3B3 dosage or structure in developmental disease, and more broadly SF3B complex dysregulation is recognized as part of the splicing-factor alteration landscape in myeloid malignancies, even though recurrent hotspot mutations more commonly affect SF3B1, U2AF1 and SRSF2 in myelodysplastic syndromes. |
