U2af1Edit

U2af1, short for U2 small nuclear RNA auxiliary factor 1, is a gene that encodes the 35-kDa subunit of the U2 auxiliary factor, a key player in the early steps of pre-mRNA splicing. In human cells, U2AF1 forms a functional partnership with U2AF2 to recognize the 3' splice site and polypyrimidine tract of nascent transcripts, guiding the assembly of the spliceosome and the accurate removal of introns. This activity is fundamental to the expression of most protein-coding genes and to the proper regulation of gene expression across tissues. For a broader context on how this fits into messenger RNA processing, see RNA splicing and pre-mRNA splicing. U2AF1 also interacts with other splicing factors, including U2AF2, to ensure fidelity of splice-site selection.

Overview of the U2AF1/U2AF2 system

U2AF1 provides RNA-binding capability through its zinc-binding domains and contributes to establishing the correct 3' splice site context. Its partner, U2AF2, binds the polypyrimidine tract, and together they recruit the early spliceosome components to the intron–exon boundary. This collaboration is a critical step before the recruitment of the branchpoint-recognition complex and the U2 small nuclear RNA U2-dependent machinery.
The U2AF1–U2AF2 heterodimer acts as a checkpoint, ensuring that only properly configured splice sites proceed to catalysis. Disruption of this coordination can lead to altered splicing patterns, which in turn can affect cell behavior and gene expression profiles in ways that are relevant to development and disease.
The gene is conserved across vertebrates, illustrating the essential nature of accurate 3' splice site recognition in multicellular organisms. Comparative studies across model organisms help illuminate how splicing fidelity is maintained and what happens when it is perturbed. See evolutionary conservation and model organisms for related discussions.

Structure, domains, and regulation

Protein architecture: U2AF1 contains RNA-binding domains that enable contact with the 3' splice site region and coordination with U2AF2. The precise arrangement of these domains supports recognition of the AG dinucleotide and neighboring sequences that mark the end of introns.
Isoforms and regulation: Alternative splicing can generate multiple U2AF1 isoforms, contributing to tissue-specific regulation of splicing or to responses to cellular stress. The expression and composition of the U2AF1/2 complex can be modulated in different cellular contexts, influencing splice-site choice and downstream gene expression.
Interactions: Beyond its partnership with U2AF2, U2AF1 participates in broader networks of splicing factors that assemble at the 3' end of introns. These interactions influence spliceosome assembly dynamics and the efficiency of intron removal.

Function in RNA splicing

Primary role: U2AF1, in conjunction with U2AF2, recognizes the 3' splice site and helps recruit the U2 snRNP to the branchpoint region. This sets the stage for subsequent steps that remove introns and join exons.
Fidelity and variability: Changes in U2AF1 function can shift splice-site selection, leading to alternative splicing events. Such shifts can alter the expression of transcripts and the production of protein variants, which may influence cell behavior, differentiation, or disease processes.
Relevance to gene expression programs: Since most transcripts undergo splicing, the activity of U2AF1 intersects with numerous cellular pathways. Disruptions or alterations in splicing patterns can have wide-reaching effects on cell physiology, including responses to stress, development, and oncogenic transformation.

Clinical significance and research context

Mutations in U2AF1 have been repeatedly observed in hematologic cancers, particularly myeloid malignancies such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). The most well-characterized variants—such as S34F and Q157P—tend to affect the RNA-binding properties of the protein and are associated with widespread, modest yet consistent alterations in splicing across transcripts.
Pathogenic impact: In cancer, altered splicing driven by U2AF1 mutations can contribute to malignant phenotypes by producing protein variants that support proliferation, survival, or evasion of normal regulatory controls. This has positioned U2AF1 and related splicing factors as a focus of research into cancer biology and potential therapeutic strategies.
Therapeutic considerations: The broader field is exploring splicing-modulating approaches and targeted therapies that can rectify or exploit mis-splicing patterns in cancer. These efforts include antisense strategies and small-molecule modulators of the spliceosome, which come with ongoing discussions about efficacy, safety, and off-target effects in clinical settings. See discussions around antisense oligonucleotide therapies and spliceosome inhibitors for related topics.
Biomarker and diagnostic implications: Given the recurrence of U2AF1 mutations in certain cancers, there is interest in using such alterations as diagnostic or prognostic biomarkers, and in understanding how splicing changes might inform treatment choices or disease monitoring.

Research resources and model systems

Experimental models: Researchers study U2AF1 function using cell lines, primary patient samples, and animal models to dissect its role in splicing and cancer biology. These models help clarify how specific mutations or expression changes influence splicing outcomes and cellular phenotypes.
Genomic and transcriptomic analyses: High-throughput sequencing methods, including RNA sequencing, are employed to map splicing changes associated with U2AF1 perturbations. Data from these studies contribute to understanding the scope and impact of U2AF1-linked mis-splicing across tissues.
Available reagents and tools: Antibodies, plasmids, and gene-editing approaches (such as CRISPR-based strategies) enable targeted investigation of U2AF1’s function and its interactions with partner factors like U2AF2 and other components of the spliceosome.