ERCC4 Gene: Structure, Function, and Clinical Significance
A comprehensive guide to the ERCC4 gene, its role in DNA repair, associated diseases, and clinical implications.
Gene Information Card
| Symbol | ERCC4 |
|---|---|
| Full Name | ERCC excision repair 4, endonuclease catalytic subunit |
| Gene Type | Protein coding |
| Chromosomal Location | 16p13.12 |
| NCBI Gene ID | 2072 ncbi.nlm.nih.gov/gene/2072 |
| Ensembl ID | ENSG00000175595 |
| UniProt ID | Q01831 |
| OMIM ID | 133520 |
| HGNC ID | 3436 |
| Aliases | XPF, RAD4, XFEPS, COFS4, MGC20637 |
Description
The ERCC4 gene encodes the ERCC4 protein, also known as XPF, which is a structure-specific endonuclease essential for nucleotide excision repair (NER) and interstrand crosslink (ICL) repair. It forms a heterodimer with ERCC1 to incise DNA on the 5' side of lesions. Mutations in ERCC4 cause a spectrum of disorders including xeroderma pigmentosum group F, Fanconi anemia complementation group Q, Cockayne syndrome, and cerebro-oculo-facio-skeletal syndrome.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Xeroderma Pigmentosum, Complementation Group F | Loss of function mutations in ERCC4 impair NER, leading to UV sensitivity and increased skin cancer risk. | ClinVar, OMIM |
| Fanconi Anemia, Complementation Group Q | ERCC4 mutations disrupt ICL repair, causing bone marrow failure and cancer predisposition. | ClinVar, OMIM |
| Cockayne Syndrome | Mutations in ERCC4 can cause a severe form of Cockayne syndrome with developmental and neurological abnormalities. | ClinVar, OMIM |
| Cerebro-Oculo-Facio-Skeletal Syndrome 4 | Biallelic ERCC4 mutations lead to this severe progeroid syndrome with multiple congenital anomalies. | ClinVar, OMIM |
| XFE Progeroid Syndrome | Specific ERCC4 mutations cause an accelerated aging phenotype with liver and kidney dysfunction. | OMIM |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Testis | 25.4 | High |
| Thyroid | 20.1 | High |
| Adrenal Gland | 18.3 | High |
| Bone Marrow | 15.2 | Medium |
| Lung | 12.8 | Medium |
| Liver | 10.5 | Medium |
| Brain | 8.9 | Low |
| Heart | 7.2 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HeLa | 18.5 | Cervical cancer cell line |
| A549 | 15.3 | Lung carcinoma |
| MCF7 | 12.1 | Breast cancer |
| HepG2 | 14.7 | Liver cancer |
| K562 | 10.2 | Leukemia |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.2395C>T (p.Arg799Trp) | Missense | Rare | Impairs ERCC1 binding and reduces endonuclease activity |
| c.2508+1G>A | Splice site | Rare | Exon skipping leading to truncated protein |
| c.1480C>T (p.Arg494Ter) | Nonsense | Rare | Premature stop codon, loss of function |
| c.2065C>T (p.Arg689Trp) | Missense | Rare | Disrupts DNA binding and catalytic activity |
Mutation functional classification
Loss of Function (LOF)
Most ERCC4 mutations are loss-of-function, leading to defective NER and ICL repair, causing XP-F and FA-Q.
Gain of Function (GOF)
No gain-of-function mutations have been reported for ERCC4.
Dominant Negative (DN)
Some missense mutations may exert dominant-negative effects by forming inactive heterodimers with ERCC1, but this is not well established.
View complete mutation data：
Gene Ontology (GO)
| • DNA endonuclease activity | • protein heterodimerization activity |
| • nucleotide-excision repair | • interstrand cross-link repair |
| • response to UV | • cell cycle checkpoint |
Pathways
• Nucleotide Excision Repair
• Fanconi Anemia Pathway
• Homologous Recombination Repair (via ICL processing)
Protein Summary
The ERCC4 protein (XPF) is a 916-amino acid endonuclease that forms a heterodimer with ERCC1. The complex cleaves DNA at the 5' side of bulky lesions during NER and at ICLs during repair. It contains a helicase-like domain and a nuclease domain. Mutations affecting its catalytic activity or interaction with ERCC1 lead to various DNA repair disorders.
Related Services
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| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| ERCC4 (p.S835=) Point Mutation in HAP1 Cell Line | EDC03466 | Human | 2072 | Details Get a Quote |
| ERCC4 (c.207+11G>A )Point Mutation in HAP1 Cell Line | EDC03465 | Human | 2072 | Details Get a Quote |
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