CUL4A (Cullin 4A): E3 Ubiquitin Ligase, Cell Cycle Regulator, and Oncogenic Driver
A comprehensive biomedical overview of the CUL4A gene, its protein function, associated diseases, expression patterns, and mutational landscape, based on authoritative genomic databases.
Gene Information Card
| Symbol | CUL4A |
|---|---|
| Full Name | Cullin 4A |
| Gene Type | protein coding |
| Chromosomal Location | 13q34 |
| NCBI Gene ID | 8451 ncbi.nlm.nih.gov/gene/8451 |
| Ensembl ID | ENSG00000139842 |
| UniProt ID | Q13619 |
| OMIM ID | 603137 |
| HGNC ID | 2554 |
| Aliases | CUL-4A, FLJ14487 |
Description
CUL4A encodes cullin-4A, a core component of the Cullin-RING E3 ubiquitin ligase complex (CRL4A). This complex ubiquitinates various substrates, including cell cycle regulators (e.g., CDT1, p21) and DNA damage response proteins (e.g., XPC, DDB2), targeting them for proteasomal degradation. CUL4A is essential for cell cycle progression, DNA replication, and DNA repair. Overexpression and genetic alterations of CUL4A are frequently observed in various cancers, contributing to tumorigenesis through dysregulation of these pathways.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Hepatocellular carcinoma | CUL4A overexpression promotes degradation of tumor suppressors (e.g., p53, p21) and enhances cell proliferation; copy number gain at 13q34 is common. | COSMIC, ClinVar, literature (e.g., Pan et al., 2013) |
| Breast cancer | Amplification and overexpression of CUL4A correlate with poor prognosis; it promotes ubiquitination of p53 and other cell cycle inhibitors, driving tumor growth. | COSMIC, ClinVar, literature (e.g., Chen et al., 2015) |
| Colorectal cancer | CUL4A upregulation is associated with advanced stage and metastasis; it regulates β-catenin degradation, affecting Wnt signaling. | COSMIC, ClinVar, literature (e.g., Wang et al., 2014) |
| Lung cancer | CUL4A overexpression in non-small cell lung cancer (NSCLC) promotes cell cycle progression and resistance to apoptosis. | COSMIC, ClinVar, literature (e.g., Li et al., 2017) |
| Gastric cancer | Elevated CUL4A expression is linked to tumor invasion and poor survival; it modulates the ubiquitination of cell cycle regulators. | COSMIC, ClinVar, literature (e.g., Zhang et al., 2018) |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Testis | 25.3 | High |
| Bone marrow | 18.7 | Medium |
| Lymph node | 15.2 | Medium |
| Spleen | 12.8 | Medium |
| Liver | 10.1 | Medium |
| Lung | 8.4 | Low |
| Brain | 6.2 | Low |
| Heart | 5.1 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HeLa (cervical cancer) | 22.5 | High expression; used in many CUL4A functional studies |
| MCF7 (breast cancer) | 18.3 | High expression; associated with estrogen receptor signaling |
| A549 (lung cancer) | 15.7 | Moderate-high; involved in DNA damage response |
| HepG2 (liver cancer) | 14.2 | Moderate; linked to hepatocarcinogenesis |
| K562 (leukemia) | 12.1 | Moderate; role in hematopoiesis |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1234A>G (p.Ile412Val) | Missense | 0.5% (COSMIC) | Unknown; likely benign, but may affect protein stability |
| c.1567C>T (p.Arg523Trp) | Missense | 0.2% (COSMIC) | Potential loss-of-function; affects substrate binding |
| c.789_790insA (frameshift) | Insertion | 0.1% (COSMIC) | Predicted loss-of-function; truncated protein |
| c.1012G>A (p.Gly338Arg) | Missense | 0.3% (ClinVar) | Uncertain significance; may alter ubiquitin ligase activity |
| Copy number gain (13q34) | Amplification | 10-15% in various cancers (COSMIC) | Gain-of-function; leads to overexpression and oncogenic activity |
Mutation functional classification
Loss of Function (LOF)
Loss-of-function mutations (e.g., frameshift, nonsense) are rare and may impair CRL4A complex formation, leading to genomic instability and cell cycle defects. However, such mutations are not commonly observed in cancers, suggesting CUL4A primarily acts as an oncogene through overexpression.
Gain of Function (GOF)
Gain-of-function is primarily achieved through gene amplification and transcriptional upregulation, leading to increased ubiquitination of tumor suppressors and enhanced cell proliferation. Specific missense mutations that increase protein stability or substrate affinity could also be gain-of-function, but these are not well characterized.
Dominant Negative (DN)
Dominant-negative mutations are not well documented for CUL4A. However, mutations that disrupt the interaction with DDB1 or RING components could potentially act in a dominant-negative manner, interfering with the function of the wild-type allele. Such mutations are rare and not clinically significant.
View complete mutation data：
Gene Ontology (GO)
| • ubiquitin-protein transferase activity | • protein ubiquitination |
| • cell cycle | • DNA damage response |
| • DNA repair | • nucleotide-excision repair |
| • G1/S transition of mitotic cell cycle | • proteasome-mediated ubiquitin-dependent protein catabolic process |
| • cullin-RING ubiquitin ligase complex | • nucleus |
Pathways
• Cullin-RING ubiquitin ligase (CRL4A) pathway
• Cell cycle regulation (G1/S transition)
• DNA damage response (Nucleotide Excision Repair)
• Ubiquitin-proteasome pathway
• p53 signaling pathway (via ubiquitination of p53)
Protein Summary
Cullin-4A (UniProt Q13619) is a 759-amino acid protein that serves as a scaffold for the CRL4A E3 ubiquitin ligase complex. It interacts with DDB1 (DNA damage-binding protein 1) and a RING finger protein (RBX1/ROC1) to form an active ligase. The complex recognizes substrates through DDB1-CUL4A-associated factors (DCAFs). CUL4A is involved in ubiquitinating key cell cycle regulators (e.g., CDT1, p21, p27) and DNA repair proteins (e.g., XPC, DDB2). Its activity is regulated by neddylation (conjugation of NEDD8) and de-neddylation. CUL4A is overexpressed in many cancers, making it a potential therapeutic target.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| CUL4A Knockout HEK293 Cell Line | EDJ-KQ3301 | Human | 8451 | Details Get a Quote |
| CUL4A Knockout A-549 Cell Line | EDJ-KQ24884 | Human | 8451 | Details Get a Quote |
| CUL4A Knockout HCT 116 Cell Line | EDJ-KQ24885 | Human | 8451 | Details Get a Quote |
| CUL4A Knockout HeLa Cell Line | EDJ-KQ24886 | Human | 8451 | Details Get a Quote |
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