Disease relevance of ERCC4

• Co-correction of the ERCC1, ERCC4 and xeroderma pigmentosum group F DNA repair defects in vitro [1].
• Thus mutations in the ERCC1 and ERCC4 genes impart a hypersensitivity to CP analogs [2].
• Our finding suggests that the combined effect of ERCC2 Asp(312)Asn and ERCC4 Ser(835)Ser genotypes might be associated with breast cancer risk in Korean women [3].
• To determine whether XPF-ERCC1 completes a set of six proteins that are sufficient to carry out excision repair, the human XPF and ERCC1 cDNAs were coexpressed in Sf21 insect cells from a baculovirus vector [4].
• Cosmid clones carrying a functional ERCC4 gene were isolated from a library of a secondary transformant by selecting in Escherichia coli for expression of a linked neomycin-resistance gene that was present in the sCos-1 vector [5].

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

• In baboon tissues, ERCC4 was expressed weakly and was not significantly higher in testis than in nonmeiotic tissues [10].
• We previously investigated 2 testis tumor cell lines with a low capacity to remove cisplatin-induced DNA damage and found that they had low levels of the DNA nucleotide excision repair proteins XPA, ERCC1 and XPF [12].
• The levels of the mRNA transcripts for ERCC1, XPF, and XPA were measured in a panel of 14 different human cancer cell lines, using real-time PCR [13].
• The cosmids mapped to 16p13.13-p13.2, the location assigned to ERCC4 by using somatic cell hybrids [5].
• Most strikingly, TC was particularly potent in inducing apoptosis of the UV41 mutant CHO cells, which are deficient in the ERCC4 gene encoding a nucleotide excision repair protein [14].

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

• Molecular cloning of the human nucleotide-excision-repair gene ERCC4 [5].
• ERCC4 Associated with Breast Cancer Risk: A Two-Stage Case-Control Study Using High-throughput Genotyping [26].
• We hypothesized that two ERCC4 single-nucleotide polymorphisms are associated with normal-tissue toxicity in patients treated with radiotherapy for oropharyngeal squamous cell carcinoma (OPSCC) [27].
• Gastrostomy in oropharyngeal cancer patients with ERCC4 (XPF) germline variants [27].
• We propose that the ternary complex of hRad52 and XPF/ERCC1 is the active species that processes recombination intermediates generated during the repair of DNA double strand breaks and in homology-dependent gene targeting events [28].

References