ERCC4 (also known as XPF) encodes a critical DNA repair endonuclease that plays a central role in nucleotide excision repair (NER). The XPF-ERCC1 heterodimer is responsible for making the 5' incision during NER, making it essential for removing bulky DNA adducts, UV-induced photoproducts, and other forms of DNA damage that would otherwise cause cell death or malignant transformation[1].
| Property | Value |
|---|---|
| Gene Symbol | ERCC4 (formerly XPF) |
| Chromosomal Location | 16p13.12 |
| NCBI Gene ID | 2072 |
| OMIM | 278760 |
| UniProt | Q92841 |
| Protein Length | 966 amino acids |
| Molecular Weight | ~104 kDa |
XPF forms a stable heterodimer with ERCC1 (ERCC1-XPF complex), which functions as a structure-specific endonuclease with precise cleavage specificity. The complex recognizes and cleaves DNA at the 5' side of various DNA lesions, including[2]:
The NER pathway operates through two sub-pathways:
XPF-ERCC1 is essential for both pathways, making the critical 5' incision that allows damaged DNA fragment removal and gap filling by DNA polymerases[3].
The ERCC1-XPF complex does not directly recognize DNA lesions but is recruited to damage sites by the XPC complex (in GG-NER) or by RNA polymerase II stalling (in TC-NER). Once recruited, the complex makes a precise incision 5-6 nucleotides upstream of the lesion, while XPG (ERCC5) makes the corresponding 3' incision. This generates a single-stranded DNA fragment containing the damage, which is then removed and the gap filled by DNA polymerases (primarily Pol δ and Pol ε)[4].
The XPF protein contains several functional domains:
The ERCC1-XPF interaction is highly specific and essential for stability - each subunit stabilizes the other, and the complex must form properly for both proteins to remain functional in the cell[5].
Biallelic mutations in ERCC4/XPF cause xeroderma pigmentosum complementation group F (XP-F), characterized by[6]:
Interestingly, XP-F patients often show milder neurological symptoms compared to other XP groups, suggesting that XPF function may be partially compensated in neural tissues or that the NER defects in neurons follow different mechanisms[7].
Some ERCC4 mutations can cause Fanconi anemia (FA) spectrum disorders, which involve:
The ERCC4 gene is designated as FANC-Q in the Fanconi anemia nomenclature[8].
Reduced XPF function has been implicated in age-related neurodegenerative diseases through multiple mechanisms[9]:
Research has shown that:
XPF is expressed in all human tissues with particularly high levels in:
The XPF protein (ERCC4) has the following domain organization[11]:
XPF mutations can be identified through:
| Partner | Function | Reference |
|---|---|---|
| ERCC1 | Heterodimer formation, substrate recognition | [13] |
| XPA | Damage verification, complex recruitment | [14] |
| XPC | Global genome NER damage recognition | [15] |
| TFIIH | Transcription-repair coupling | [16] |
Friedberg et al. DNA Repair and Mutagenesis (2006). 2006. ↩︎
Scharer, "Nucleotide excision repair in eukaryotes" (2008). Cold Spring Harbor Perspectives in Biology. 2008. ↩︎
F和在ab, "Molecular mechanisms of nucleotide excision repair" (2009). 2009. ↩︎
Reardon and Sancar, "Formation and repair of cyclobutane pyrimidine dimers" (2006). 2006. ↩︎
Tsodikov et al. "Structure of the ERCC1-XPF heterodimer" (2007). 2007. ↩︎
Kraemer et al. "Xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy" (2007). 2007. ↩︎
Anttinen et al. "Neurological symptoms in XP-F patients" (2008). 2008. ↩︎
Garcia-Morque et al. "ERCC4 and Fanconi anemia" (2014). 2014. ↩︎
Kelley et al. "DNA repair in neurons: Implications for neurodegeneration" (2011). 2011. ↩︎
Jacobson et al. "DNA damage and repair in Alzheimer's disease" (2010). 2010. ↩︎
Tripsianes et al. "Domain architecture of XPF" (2011). 2011. ↩︎
Arora et al. "XPF deficiency and chemotherapy sensitivity" (2010). 2010. ↩︎
de Laat et al. "ERCC1-XPF heterodimer structure" (1998). 1998. ↩︎
Nocentini et al. "XPA-XPF interaction in NER" (1999). 1999. ↩︎
Sugasawa et al. "XPC-XPF recruitment in GG-NER" (2001). 2001. ↩︎
Coin et al. "TFIIH and NER" (2008). 2008. ↩︎