UBA2: Ubiquitin-Like Modifier Activating Enzyme 2
A key component of the SUMOylation pathway involved in cellular signaling, cell cycle regulation, and cancer.
Gene Information Card
| Symbol | UBA2 |
|---|---|
| Full Name | ubiquitin-like modifier activating enzyme 2 |
| Gene Type | protein-coding |
| Chromosomal Location | 19q13.11 |
| NCBI Gene ID | 10054 ncbi.nlm.nih.gov/gene/10054 |
| Ensembl ID | ENSG00000126261 |
| UniProt ID | Q9UBT2 |
| OMIM ID | 613295 |
| HGNC ID | 12461 |
| Aliases | SAE2, UBLE1B, SUMO-activating enzyme subunit 2 |
Description
UBA2 (ubiquitin-like modifier activating enzyme 2) encodes the larger subunit of the heterodimeric SUMO-activating enzyme (SAE1/SAE2). This enzyme catalyzes the first step in SUMOylation, a post-translational modification essential for nuclear transport, transcriptional regulation, DNA repair, and cell cycle progression. UBA2 forms a thioester bond with SUMO (small ubiquitin-like modifier) in an ATP-dependent manner, transferring SUMO to the conjugating enzyme UBE2I. Dysregulation of UBA2 expression or function is implicated in various cancers and developmental disorders.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Colorectal cancer | Overexpression of UBA2 promotes cell proliferation and invasion via enhanced SUMOylation of oncogenic targets. | ClinVar, COSMIC |
| Acute myeloid leukemia | Recurrent mutations and altered expression of UBA2 disrupt SUMOylation of transcription factors involved in hematopoiesis. | COSMIC, NCBI Gene |
| Prostate cancer | UBA2 amplification correlates with poor prognosis and androgen receptor signaling dysregulation. | COSMIC, OMIM |
| Developmental delay / intellectual disability | De novo missense variants in UBA2 impair SUMO-activating enzyme activity, affecting neuronal development. | ClinVar, OMIM |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Testis | 18.5 | High |
| Lymph node | 12.3 | Medium |
| Bone marrow | 10.8 | Medium |
| Brain | 6.2 | Low |
| Liver | 5.1 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HeLa | 15.2 | Cervical cancer cell line |
| K562 | 14.0 | Leukemia cell line |
| A549 | 11.5 | Lung cancer cell line |
| MCF7 | 9.8 | Breast cancer cell line |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1135C>T (p.Arg379Cys) | Missense | 0.02% (gnomAD) | Reduced SUMO-activating enzyme activity; associated with developmental disorders |
| c.1486G>A (p.Glu496Lys) | Missense | 0.01% (gnomAD) | Impaired ATP binding and SUMO activation |
| c.1720_1721insA (p.Thr574Asnfs*2) | Frameshift | 0.005% (COSMIC) | Loss of function; observed in colorectal cancer |
| Amplification (copy number gain) | Copy number variation | 5-10% (COSMIC) | Overexpression; linked to prostate and breast cancer |
Mutation functional classification
Loss of Function (LOF)
Frameshift and nonsense mutations (e.g., p.Thr574Asnfs*2) truncate the protein, abolishing SUMO-activating enzyme activity and disrupting SUMOylation.
Gain of Function (GOF)
Amplification and overexpression of wild-type UBA2 lead to increased SUMOylation of oncoproteins, promoting cell proliferation and tumorigenesis.
Dominant Negative (DN)
Missense mutations (e.g., p.Arg379Cys) produce a defective subunit that binds SAE1 but fails to activate SUMO, interfering with the wild-type enzyme complex.
View complete mutation data：
Gene Ontology (GO)
Pathways
• SUMOylation (Reactome: R-HSA-2990846)
• SUMO E3 ligases SUMOylate target proteins (Reactome: R-HSA-3108232)
• Cellular responses to stress (Reactome: R-HSA-2262752)
Protein Summary
UBA2 (SAE2) is the catalytic subunit of the SUMO-activating enzyme (SAE1/SAE2 heterodimer). It contains an ATP-binding domain and a catalytic cysteine (Cys173) that forms a thioester intermediate with SUMO. The protein is predominantly nuclear and essential for SUMO conjugation to target proteins. Structural studies show that UBA2 adopts a two-domain architecture: an N-terminal domain that interacts with SAE1 and a C-terminal domain that binds SUMO and ATP. Mutations in UBA2 impair SUMOylation, leading to genomic instability and altered cell signaling.
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