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Gene Review

ERCC4  -  excision repair cross-complementation group 4

Homo sapiens

Synonyms: DNA excision repair protein ERCC-4, DNA repair endonuclease XPF, DNA repair protein complementing XP-F cells, ERCC11, FANCQ, ...
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Disease relevance of ERCC4


High impact information on ERCC4

  • Telomere loss in these mice was mediated by XPF, a structure-specific nuclease involved in ultraviolet-induced damage repair and mutated in individuals with xeroderma pigmentosum [6].
  • The XPF protein was purified from mammalian cells in a tight complex with ERCC1 [7].
  • Ultraviolet light-induced DNA damage caused a transient dose-dependent immobilization of ERCC1/XPF, likely due to engagement of the complex in a single repair event [8].
  • The XPF/Mus81 structure-specific endonucleases cleave double-stranded DNA (dsDNA) within asymmetric branched DNA substrates and play an essential role in nucleotide excision repair, recombination and genome integrity [9].
  • We identify two nonequivalent DNA-binding sites and propose a model in which XPF distorts the 3' flap substrate in order to engage both binding sites and promote strand cleavage [9].

Biological context of ERCC4

  • The ERCC4 gene, assigned to chromosome 16p13.1-p13.2, was previously isolated by using a chromosome 16 cosmid library [10].
  • The considerable identity (40%) between ERCC4 and MEI-9 suggests a possible involvement of ERCC4 in meiosis [10].
  • XRCC3,XRCC1, ERCC4, and XPD-ERCC1 haplotype frequencies were estimated by the maximum likelihood method [11].
  • CONCLUSIONS: Our findings confirm the general pattern indicating that the ERCC1 and ERCC4 gene products are crucial for the repair of 4HC-induced DNA damage, while the other nucleotide excision repair genes examined are relatively unimportant [2].
  • Furthermore, two interspecific hybrids derived from UV41, both of which retained the region of human chromosome 16 that harbors the ERCC4 gene, displayed essentially wild-type resistance to 4HC and PM, confirming the importance of ERCC4 for the repair of 4HC-induced DNA damage [2].

Anatomical context of ERCC4


Associations of ERCC4 with chemical compounds

  • In GSH-depleted cells, the down-regulation of ERCC1 expression by H(2)O(2) was completely abolished and the up-regulation of ERCC4 expression was potentiated from 2.5-fold to >10-fold [15].
  • The XPF and ERCC1 proteins form a tight complex and function as an endonuclease to incise on the 5'-side of pyrimidine dimers in DNA [16].
  • XPF extracts are highly defective in the stimulation of repair synthesis by N:-acetoxy-N:- acetylaminofluorene, but are proficient in the stimulation of DNA synthesis by psoralen interstrand crosslinks [17].
  • In addition, the survival of normal cells after chrysotile exposure increases with time if they are kept from replicating, while the survival of XPF cells under the same circumstances does not change [18].
  • XP-F cells showed somewhat higher sensitivity to formaldehyde, possibly signaling participation of XPF protein in the removal of residual peptide-DNA adducts [19].

Physical interactions of ERCC4

  • We have made a replication-defective adenovirus, AdCMV-FlagXPA(59-114), that expresses a truncated form of XPA encompassing amino acids 59-114 sufficient for binding to the excision repair cross-complementing protein 1 (ERCC1)/xeroderma pigmentosum complementation group F (XPF) nuclease essential for making an incision 5' of the damage [20].

Regulatory relationships of ERCC4

  • Although XP-F cells are sensitive to UV and mitomycin C (MMC), cells overexpressing XPF expressed ERCC1 as well and resistance to UV and MMC was restored to the normal level [16].
  • Here we report that TRF2-induced telomere shortening is abrogated in human cells deficient in XPF, demonstrating that XPF-ERCC1 is required for TRF2-promoted telomere shortening [21].

Other interactions of ERCC4

  • Both XPE and XPF proteins have functions separate from their role in NER, but the exact nature of these functions has not yet been established [22].
  • Such dispersal requires functional XPA, XPF and XPG proteins [23].
  • Reduced levels of XPA, ERCC1 and XPF DNA repair proteins in testis tumor cell lines [12].
  • Compared with the controls, the cases had lower expression levels for all the NER proteins, particularly XPC and XPF, which were reduced by about 25% (P<0.01) [24].
  • The PCNA-XPF complex acts as a structure-specific nuclease on a similar range of DNA flap, bubble and junction substrates as the human protein, suggesting a fundamental conservation through billions of years of evolution [25].

Analytical, diagnostic and therapeutic context of ERCC4


  1. Co-correction of the ERCC1, ERCC4 and xeroderma pigmentosum group F DNA repair defects in vitro. Biggerstaff, M., Szymkowski, D.E., Wood, R.D. EMBO J. (1993) [Pubmed]
  2. Nucleotide excision repair genes as determinants of cellular sensitivity to cyclophosphamide analogs. Andersson, B.S., Sadeghi, T., Siciliano, M.J., Legerski, R., Murray, D. Cancer Chemother. Pharmacol. (1996) [Pubmed]
  3. Obesity and genetic polymorphism of ERCC2 and ERCC4 as modifiers of risk of breast cancer. Lee, S.A., Lee, K.M., Park, W.Y., Kim, B., Nam, J., Yoo, K.Y., Noh, D.Y., Ahn, S.H., Hirvonen, A., Kang, D. Exp. Mol. Med. (2005) [Pubmed]
  4. Reconstitution of human excision nuclease with recombinant XPF-ERCC1 complex. Bessho, T., Sancar, A., Thompson, L.H., Thelen, M.P. J. Biol. Chem. (1997) [Pubmed]
  5. Molecular cloning of the human nucleotide-excision-repair gene ERCC4. Thompson, L.H., Brookman, K.W., Weber, C.A., Salazar, E.P., Reardon, J.T., Sancar, A., Deng, Z., Siciliano, M.J. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  6. XPF nuclease-dependent telomere loss and increased DNA damage in mice overexpressing TRF2 result in premature aging and cancer. Muñoz, P., Blanco, R., Flores, J.M., Blasco, M.A. Nat. Genet. (2005) [Pubmed]
  7. Xeroderma pigmentosum group F caused by a defect in a structure-specific DNA repair endonuclease. Sijbers, A.M., de Laat, W.L., Ariza, R.R., Biggerstaff, M., Wei, Y.F., Moggs, J.G., Carter, K.C., Shell, B.K., Evans, E., de Jong, M.C., Rademakers, S., de Rooij, J., Jaspers, N.G., Hoeijmakers, J.H., Wood, R.D. Cell (1996) [Pubmed]
  8. Action of DNA repair endonuclease ERCC1/XPF in living cells. Houtsmuller, A.B., Rademakers, S., Nigg, A.L., Hoogstraten, D., Hoeijmakers, J.H., Vermeulen, W. Science (1999) [Pubmed]
  9. Structure of an XPF endonuclease with and without DNA suggests a model for substrate recognition. Newman, M., Murray-Rust, J., Lally, J., Rudolf, J., Fadden, A., Knowles, P.P., White, M.F., McDonald, N.Q. EMBO J. (2005) [Pubmed]
  10. ERCC4 (XPF) encodes a human nucleotide excision repair protein with eukaryotic recombination homologs. Brookman, K.W., Lamerdin, J.E., Thelen, M.P., Hwang, M., Reardon, J.T., Sancar, A., Zhou, Z.Q., Walter, C.A., Parris, C.N., Thompson, L.H. Mol. Cell. Biol. (1996) [Pubmed]
  11. Polymorphisms/haplotypes in DNA repair genes and smoking: a bladder cancer case-control study. Matullo, G., Guarrera, S., Sacerdote, C., Polidoro, S., Davico, L., Gamberini, S., Karagas, M., Casetta, G., Rolle, L., Piazza, A., Vineis, P. Cancer Epidemiol. Biomarkers Prev. (2005) [Pubmed]
  12. Reduced levels of XPA, ERCC1 and XPF DNA repair proteins in testis tumor cell lines. Welsh, C., Day, R., McGurk, C., Masters, J.R., Wood, R.D., Köberle, B. Int. J. Cancer (2004) [Pubmed]
  13. Regulation of DNA repair gene expression in human cancer cell lines. McGurk, C.J., Cummings, M., Köberle, B., Hartley, J.A., Oliver, R.T., Masters, J.R. J. Cell. Biochem. (2006) [Pubmed]
  14. c-Myc degradation induced by DNA damage results in apoptosis of CHO cells. Jiang, M.R., Li, Y.C., Yang, Y., Wu, J.R. Oncogene (2003) [Pubmed]
  15. The role of glutathione in the regulation of nucleotide excision repair during oxidative stress. Langie, S.A., Knaapen, A.M., Houben, J.M., van Kempen, F.C., de Hoon, J.P., Gottschalk, R.W., Godschalk, R.W., van Schooten, F.J. Toxicol. Lett. (2007) [Pubmed]
  16. Sensitivity of group F xeroderma pigmentosum cells to UV and mitomycin C relative to levels of XPF and ERCC1 overexpression. Yagi, T., Katsuya, A., Koyano, A., Takebe, H. Mutagenesis (1998) [Pubmed]
  17. Differential processing of UV mimetic and interstrand crosslink damage by XPF cell extracts. Zhang, N., Zhang, X., Peterson, C., Li, L., Legerski, R. Nucleic Acids Res. (2000) [Pubmed]
  18. Xeroderma pigmentosum fibroblasts are more sensitive to asbestos fibers than are normal human fibroblasts. Yang, L.L., Kouri, R.E., Curren, R.D. Carcinogenesis (1984) [Pubmed]
  19. Loss of DNA-protein crosslinks from formaldehyde-exposed cells occurs through spontaneous hydrolysis and an active repair process linked to proteosome function. Quievryn, G., Zhitkovich, A. Carcinogenesis (2000) [Pubmed]
  20. A truncated human xeroderma pigmentosum complementation group A protein expressed from an adenovirus sensitizes human tumor cells to ultraviolet light and cisplatin. Rosenberg, E., Taher, M.M., Kuemmerle, N.B., Farnsworth, J., Valerie, K. Cancer Res. (2001) [Pubmed]
  21. XPF with mutations in its conserved nuclease domain is defective in DNA repair but functions in TRF2-mediated telomere shortening. Wu, Y., Zacal, N.J., Rainbow, A.J., Zhu, X.D. DNA Repair (Amst.) (2007) [Pubmed]
  22. DNA repair-deficient diseases, xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy. Lehmann, A.R. Biochimie (2003) [Pubmed]
  23. Tumor suppressor p53 dependent recruitment of nucleotide excision repair factors XPC and TFIIH to DNA damage. Wang, Q.E., Zhu, Q., Wani, M.A., Wani, G., Chen, J., Wani, A.A. DNA Repair (Amst.) (2003) [Pubmed]
  24. Expression of nucleotide excision repair proteins in lymphocytes as a marker of susceptibility to squamous cell carcinomas of the head and neck. Wei, Q., Wang, L.E., Sturgis, E.M., Mao, L. Cancer Epidemiol. Biomarkers Prev. (2005) [Pubmed]
  25. An archaeal XPF repair endonuclease dependent on a heterotrimeric PCNA. Roberts, J.A., Bell, S.D., White, M.F. Mol. Microbiol. (2003) [Pubmed]
  26. ERCC4 Associated with Breast Cancer Risk: A Two-Stage Case-Control Study Using High-throughput Genotyping. Milne, R.L., Ribas, G., Gonz??lez-Neira, A., Fagerholm, R., Salas, A., Gonz??lez, E., Dopazo, J., Nevanlinna, H., Robledo, M., Ben??tez, J. Cancer Res. (2006) [Pubmed]
  27. Gastrostomy in oropharyngeal cancer patients with ERCC4 (XPF) germline variants. Kornguth, D.G., Garden, A.S., Zheng, Y., Dahlstrom, K.R., Wei, Q., Sturgis, E.M. Int. J. Radiat. Oncol. Biol. Phys. (2005) [Pubmed]
  28. Physical and functional interaction between the XPF/ERCC1 endonuclease and hRad52. Motycka, T.A., Bessho, T., Post, S.M., Sung, P., Tomkinson, A.E. J. Biol. Chem. (2004) [Pubmed]
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