U2 small nuclear ribonucleoprotein complex (U2 snRNP)

The U2 small nuclear ribonucleoprotein complex (U2 snRNP) is a fundamental component of the major spliceosome, playing a pivotal role in the processing of precursor messenger RNA (pre-mRNA) in eukaryotic cells. Its primary biological function is to recognize and bind the branch point sequence (BPS) within introns, a step that is essential for the catalytic activation of the spliceosome (UniProt, Wikipedia). The complex is composed of the U2 snRNA and several protein subunits, including the SF3A and SF3B complexes; the latter contains SF3B1, which is frequently mutated in various malignancies. In cancers such as myelodysplastic syndromes (MDS) and chronic lymphocytic leukemia (CLL), mutations in SF3B1 lead to the use of cryptic 3' splice sites, resulting in aberrant transcripts and contributing to oncogenesis (Pellagatti et al., 2018, PubMed). Therapeutic targeting of the U2 snRNP, specifically through the SF3B1 subunit, has emerged as a strategy to exploit the dependency of mutant cells on splicing fidelity. Small molecule modulators like H3B-8800 and pladienolide derivatives bind to the SF3B complex, disrupting pre-mRNA splicing and selectively inducing lethality in cells with spliceosome mutations (Seiler et al., 2018, Nature Medicine). However, because splicing is a universal cellular process, achieving a therapeutic window that avoids systemic toxicity remains a significant clinical challenge.

Other names

U2 ribonucleoproteinU2 snRNP complexSF3B complex (subunit)SF3A complex (subunit)Spliceosome U2 subcomplex

Binding and inhibition of the SF3B subunit (specifically SF3B1) within the U2 snRNP to disrupt the recognition of the branch point sequence, leading to defective splicing and induction of apoptosis in spliceosome-mutant cells.