U2AF1

U2 small nuclear RNA auxiliary factor 1, commonly referred to as U2AF1 or U2AF35, is a human gene that encodes the 35-kilodalton subunit of the U2 auxiliary factor (U2AF). U2AF operates as a heterodimer composed of U2AF1 (the small subunit) and U2AF2 (the large subunit) and plays a central role in pre-mRNA splicing, a process that removes introns from transcripts.

Functionally, U2AF1 contributes to recognition of the 3' splice site during spliceosome assembly. It binds to the AG dinucleotide at the end of introns and, in cooperation with U2AF2, helps recruit the U2 small nuclear ribonucleoprotein (snRNP) to the branch point, facilitating proper 3' splice-site selection and spliceosome formation. U2AF1 contains two zinc finger motifs that are essential for RNA binding, and its activity is modulated by interactions with other splicing factors.

The protein is encoded by a gene that undergoes alternative splicing, producing multiple isoforms that may differ in localization and interaction patterns. U2AF1 is broadly expressed across tissues and can be regulated by post-translational modifications, such as phosphorylation, which can influence splice-site choice in a context-dependent manner.

Clinical significance is most prominently associated with hematologic malignancies. Recurrent somatic mutations in U2AF1, including S34F, S34Y, and Q157R, have been identified in myelodysplastic syndromes and acute myeloid leukemia. These alterations disrupt 3' splice site recognition and generate widespread splicing abnormalities, contributing to disease pathogenesis and clonal hematopoiesis. Beyond cancer, U2AF1 variants and mis-splicing events are studied for their broader impact on gene expression programs.

Overall, U2AF1 is a conserved, essential component of the splicing machinery, influencing the fidelity of mRNA processing and linking splicing defects to disease.