u2af2

u2af2

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#f8f9fa;text-align:center;font-size:1.1em;">U2AF2</th></tr>
<tr><th>Symbol</th><td>U2AF2</td></tr>
<tr><th>Full Name</th><td>U2AF Auxiliary Factor 2</td></tr>
<tr><th>Chromosome</th><td>19q13.42</td></tr>
<tr><th>NCBI Gene ID</th><td>[11321](https://www.ncbi.nlm.nih.gov/gene/11321)</td></tr>
<tr><th>OMIM</th><td>[605024](https://www.omim.org/entry/605024)</td></tr>
<tr><th>Ensembl</th><td>[ENSG00000163251](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000163251)</td></tr>
<tr><th>UniProt</th><td>[P26368](https://www.uniprot.org/uniprot/P26368)</td></tr>
<tr><th>Associated Diseases</th><td>Amyotrophic Lateral Sclerosis (ALS), Parkinson's Disease, Alzheimer's Disease, Myelodysplastic Syndromes</td></tr>
</table>
</div>

Overview

u2af2

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#f8f9fa;text-align:center;font-size:1.1em;">U2AF2</th></tr>
<tr><th>Symbol</th><td>U2AF2</td></tr>
<tr><th>Full Name</th><td>U2AF Auxiliary Factor 2</td></tr>
<tr><th>Chromosome</th><td>19q13.42</td></tr>
<tr><th>NCBI Gene ID</th><td>[11321](https://www.ncbi.nlm.nih.gov/gene/11321)</td></tr>
<tr><th>OMIM</th><td>[605024](https://www.omim.org/entry/605024)</td></tr>
<tr><th>Ensembl</th><td>[ENSG00000163251](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000163251)</td></tr>
<tr><th>UniProt</th><td>[P26368](https://www.uniprot.org/uniprot/P26368)</td></tr>
<tr><th>Associated Diseases</th><td>Amyotrophic Lateral Sclerosis (ALS), Parkinson's Disease, Alzheimer's Disease, Myelodysplastic Syndromes</td></tr>
</table>
</div>

Overview

U2AF2 (U2AF Auxiliary Factor 2), also known as U2AF65, is a core spliceosomal protein essential for the recognition of the 3' splice site during pre-mRNA splicing. Located on chromosome 19q13.42, U2AF2 encodes a 475-amino acid protein that functions as the larger subunit of the U2AF heterodimer, with U2AF1 (U2AF35) serving as the smaller subunit. Together, these proteins recognize the polypyrimidine tract and the 3' splice site AG dinucleotide, facilitating the recruitment of the U2 small nuclear ribonucleoprotein (snRNP) to the branch point [@zhang1990].

U2AF2 plays a fundamental role in the spliceosome assembly cascade, one of the most complex and regulated processes in eukaryotic gene expression. The protein recognizes the consensus sequences at the 3' splice site and coordinates the sequential assembly of spliceosomal components. Beyond its canonical splicing function, U2AF2 has been implicated in various aspects of RNA metabolism, including mRNA transport, translation regulation, and RNA stability. These functions have made U2AF2 increasingly relevant to our understanding of neurodegenerative diseases, where RNA processing defects are recognized as central pathological mechanisms [@brooks2015].

Molecular Function and Mechanism

Role in Spliceosome Assembly

U2AF2 is a critical component of the early spliceosome assembly pathway:

Assembly Sequence:

Structural Features

The U2AF2 protein contains several functional domains:

• N-terminal RS domain: Arginine-serine repeats for protein-protein interactions
• RNA recognition motif (RRM) domains: Multiple RRMs for RNA binding
• Polypyrimidine tract binding region: Specific recognition element
• U2AF homology motif (UHM): Interfaces with U2AF1

RNA Binding Specificity

U2AF2 recognizes specific sequence elements:

• Polypyrimidine tract: Stretch of 10-20 pyrimidines (U/C) preceding the splice site
• 3' AG dinucleotide: The absolutely conserved terminal nucleotides
• Branch point recognition: Coordinates with branch point binding proteins
• Exonic splicing enhancers (ESEs): Interacts with SR proteins

Interaction Network

U2AF2 interacts with multiple spliceosomal components:

• U2AF1 (U2AF35): The heterodimer partner
• U2AF1L4/L5: Related family members
• SF3B complex: Core U2 snRNP component
• SF1/BBP: Branch point binding protein
• SR proteins: Serine/arginine-rich splicing factors
• hnRNPs: Heterogeneous nuclear ribonucleoproteins

Disease Associations

Amyotrophic Lateral Sclerosis (ALS)

U2AF2 dysfunction is highly relevant to ALS pathogenesis:

Splicing Alterations:

• SOD1 splicing defects: Altered exon skipping in ALS models
• TDP-43 pathology: Affects U2AF2 function through aggregation
• FUS interactions: RNA-binding protein pathology
• C9orf72 repeat effects: RNA toxicity affecting splicing

• Global splicing dysregulation: Extensive changes in ALS spinal cord
• Motor neuron-specific defects: Vulnerability of motor neurons
• Stress granule formation: Aberrant RNA granule dynamics
• RNA transport defects: Impaired mRNA localization

• Splicing modulators: ASOs targeting specific splicing events
• SR protein modulators: Manipulating splicing regulators
• Gene therapy: Delivering functional U2AF2

Parkinson's Disease

RNA splicing alterations in PD include U2AF2 involvement:

• Dopaminergic gene splicing: Altered patterns in PD brain
• α-Synuclein interactions: RNA-binding protein relationships
• Parkin and PINK1 splicing: Mitochondrial quality control genes
• LRRK2 splicing: PD-associated gene variants

Alzheimer's Disease

Splicing factors are implicated in AD:

• Tau splicing: Alternative splicing of MAPT gene
• APP splicing: Amyloid precursor protein isoforms
• BACE1 splicing: β-secretase variants
• Synaptic protein splicing: Neural function genes

Myelodysplastic Syndromes

U2AF2 mutations are found in MDS:

• Somatic mutations: Identified in MDS patient samples
• Splicing disruption: Altered splicing of critical genes
• Disease progression: Correlates with outcome
• Therapeutic targeting: Splicing modulators in trials

Expression Pattern

Tissue Distribution

U2AF2 is ubiquitously expressed with highest levels in:

• Brain: Particularly in neurons
• Testis: High in germ cells
• Muscle: Skeletal muscle expression
• Heart: Cardiac muscle
• Kidney: Renal tissue

Brain Expression

• Motor cortex: Pyramidal neurons
• Spinal cord: Anterior horn cells (motor neurons)
• Hippocampus: Pyramidal neurons
• Cerebellum: Purkinje cells
• Substantia nigra: Dopaminergic neurons

Cellular Localization

• Nucleus: Primary localization
• Nuclear speckles: Splicing factor storage
• Nucleolus: Some functions reported

Therapeutic Implications

Splice-Targeting Therapies

• Target disease-causing splice events
• Deliver to CNS via intrathecal delivery
• Several in clinical trials for ALS

• Splicing factor modulators
• SR protein-targeting compounds
• FDA-approved splicing modulators (e.g., nusinersen)

• Delivering functional splicing factors
• CRISPR-based corrections

Interaction Network

U2AF2 interacts with:

• U2AF1: Heterodimer partner
• SF3B1/2/3/4: U2 snRNP components
• SF1: Branch point binding protein
• SR proteins: Splicing regulators
• hnRNPs: RNA-binding proteins

Diagnostic Significance

• Mutation screening: In splicing factor-related diseases
• Biomarker potential: Expression as disease indicator

Cross-Links

• [RNA Splicing](/mechanisms/rna-splicing)
• [Spliceosome](/mechanisms/spliceosome)
• [Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)
• [Parkinson's Disease](/diseases/parkinsons-disease)

See Also

• [U2AF1 Gene](/genes/u2af1)
• [RNA Splicing Factors](/mechanisms/rna-splicing)
• [ALS](/diseases/amyotrophic-lateral-sclerosis)

External Links

• [NCBI Gene: U2AF2](https://www.ncbi.nlm.nih.gov/gene/11321)
• [UniProt: P26368](https://www.uniprot.org/uniprot/P26368)
• [Ensembl: ENSG00000163251](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000163251)
• [OMIM: 605024](https://www.omim.org/entry/605024)

References