Disease relevance of ERCC1

• To study the nuclear organization and dynamics of nucleotide excision repair (NER), the endonuclease ERCC1/XPF (for excision repair cross complementation group 1/xeroderma pigmentosum group F) was tagged with green fluorescent protein and its mobility was monitored in living Chinese hamster ovary cells [1].
• 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 [2].
• No humans with a defect in the ERCC1 subunit of this protein complex have been identified and ERCC1-deficient mice suffer from severe developmental problems and signs of premature aging on top of a repair-deficient phenotype [3].
• CONCLUSION: Our findings suggest that genetic polymorphisms of RAD52, ERCC1, and hMLH1 may be associated with breast cancer risk in Korean women [4].
• High gene expression of TS1, GSTP1, and ERCC1 are risk factors for survival in patients treated with trimodality therapy for esophageal cancer [5].

High impact information on ERCC1

• The XPF protein was purified from mammalian cells in a tight complex with ERCC1 [6].
• Human cell extracts were fractionated to locate active components, including xeroderma pigmentosum (XP) and ERCC factors [7].
• Mice with DNA repair gene (ERCC-1) deficiency have elevated levels of p53, liver nuclear abnormalities and die before weaning [8].
• Mice with defective DNA repair were generated by targeting the excision repair cross complementing gene (ERCC-1) in the embryonic stem cell line, HM-1 [8].
• Homozygous ERCC-1 mutants were runted at birth and died before weaning with liver failure [8].

Chemical compound and disease context of ERCC1

• In this study, we used synthetic siRNAs targeted to XPA and ERCC1 and compared their effectiveness in sensitising mismatch repair deficient prostate cancer cell lines to cisplatin and mitomycin C [9].
• In the present study, we have examined the potential correlation and predictive value of ERCC1, RRM1, and XPD mRNA expression in resected specimens from 67 stage IIB, IIIA, and IIIB non-small cell lung cancer patients treated with neoadjuvant gemcitabine/platinum followed by surgery [10].
• ERCC1 and thymidylate synthase mRNA levels predict survival for colorectal cancer patients receiving combination oxaliplatin and fluorouracil chemotherapy [11].
• In oxaliplatin-resistant cells, we noted increased mRNA levels of the nucleotide excision repair gene ERCC1 and ATP-binding cassette transporter breast cancer resistance protein [12].
• Alterations in gene expression, protein expression and polymorphic variants in genes encoding thymidylate synthase, dihydropyrimidine dehydrogenase, and thymidine phosphorylase and excision repair cross-complementing genes (ERCC1) may be useful as markers for clinical drug response, survival and host toxicity [13].

Biological context of ERCC1

• Action of DNA repair endonuclease ERCC1/XPF in living cells [1].
• 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 [1].
• We speculate that TDMs are formed through the recombination of telomeres with interstitial telomere-related sequences and that ERCC1/XPF functions to repress this process [14].
• Finally, the phosphorylation of XPB-S751 does not impair the TFIIH unwinding of the DNA around the lesion, but rather prevents the 5' incision triggered by the ERCC1-XPF endonuclease [15].
• A long-range restriction map of the human chromosome 19q13 region: close physical linkage between CKMM and the ERCC1 and ERCC2 genes [16].

Anatomical context of ERCC1

• Immunoblotting revealed that the testis tumour cells had normal amounts of most NER proteins, but low levels of the xeroderma pigmentosum group A protein (XPA) and the ERCC1-XPF endonuclease complex [17].
• A complex, which consists of ERCC1 (38 kDa) and a 112-kDa protein, was purified from HeLa cells to homogeneity [18].
• Comparison of the IC50 values for irofulven, cisplatin, and ecteinascidin 743 with the expression levels of ERCC1, XPD, and XPG genes in different solid tumor cell lines shows no correlation between the expression levels of any of the three nucleotide excision repair proteins and the sensitivity to ecteinascidin 743 [19].
• ERCC1 mutations in UV-sensitive Chinese hamster ovary (CHO) cell lines [20].
• However, our results indicate that ERCC1 and XPD mRNA levels may be used as a proxy for DNA repair capacity in lymphocytes [21].

Associations of ERCC1 with chemical compounds

• Possible markers of platinum chemotherapy association [glutathione S-transferase pi (GSTP1) and excision cross-complementing gene 1 (ERCC1)] and 5-fluorouracil association [thymidylate synthase 1 (TS1)] were measured [5].
• However, the effects of RAD52 2259 CT or TT and ERCC1 354 CT or TT genotypes were more evident for the estrogen/progesterone receptor-negative cases (OR, 2.03; 95% CI, 1.24-3.34 and OR, 1.99; 95% CI, 1.35-2.94, respectively) [4].
• Among the subunits, the expression of ERCC1 in WI38 cells was up-regulated significantly after emodin treatment [22].
• To confirm the importance of the ERCC1 gene for cellular resistance to 4HC and PM, UV20 cells were transfected with the human ERCC1 gene and subsequently exposed to 4HC and PM [23].
• Inhibition of transcription by DRB abolished the radiation-induced increase of ERCC1 and XRCC1 proteins [24].

Physical interactions of ERCC1

• The XPA-bound fraction complemented cell-free extracts of excision repair cross-complementing 1 (ERCC-1), ERCC-4 (XP-F), and XP-A mutants [25].
• XPG binding stabilizes the NER preincision complex and is essential for the 5' incision by the ERCC1/XPF endonuclease [26].
• Our results provide the first insights into how HMGA2 and its aberrant forms bind and regulate the ERCC1 promoter [27].
• High mobility group A2 protein and its derivatives bind a specific region of the promoter of DNA repair gene ERCC1 and modulate its activity [27].

Enzymatic interactions of ERCC1

• In mammalian cells XPG cleaves 3' of the DNA lesion while the ERCC1-XPF complex makes the 5' incision [28].

Regulatory relationships of ERCC1

• 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 [29].
• Furthermore, the regulatory effect of HMGA2 was confirmed by luciferase promoter assays showing that ERCC1 promoter activity is down-regulated by all investigated HMGA2 forms, with the most striking effect exerted by DeltaHMGA2 [27].
• Among molecular explanatory factors that were examined, the combination gefitinib-radiation therapy totally abolishes DNA-dependent protein kinase expression, and gefitinib attenuates the radiation therapy-induced enhancement of ERCC1 and augments the VTKI-induced CD95 enhancement [30].
• IL-1 alpha inhibited cisplatin induction of ERCC-1 mRNA levels in our system [31].

Other interactions of ERCC1

• 4. The minimum area of overlap shared by the interstitial deletions is between APOC2 and HRC, including ERCC1, DM, and D19S112 [32].
• Large heterology repair in nuclear extracts of human cells is also independent of the XPF gene product, and extracts of Chinese hamster ovary cells deficient in the ERCC1 and ERCC4 gene products also support the reaction [33].
• MUS81 has sequence homology to another DNA nuclease, XPF, which, with its partner ERCC1, makes the 5' incision during nucleotide excision repair [34].
• In a multivariate analysis, only XRCC1 R399Q and ERCC1 19007T>C remained significant [35].
• In multivariate analyses, TS1 >6.0, ERCC1 >3, and GSTP1 >3 were statistically significant predictors of decreased survival (P = 0.007) [5].

Analytical, diagnostic and therapeutic context of ERCC1

• 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 [36].
• His leukaemic blasts showed a reduced expression of ERCC1 protein by Western blotting [37].
• Blasts from one patient with acute mixed lineage leukaemia revealed an abnormally migrated product of the ERCC1 gene by RT-PCR [37].
• Therefore, we suggest that the C/C genotype in codon 118 of ERCC1 is a surrogate marker for predicting better survival in non-small-cell lung cancer patients treated with cisplatin combination chemotherapy [38].
• Southern blot analyses of Pst I digests of DNA from 6 bone-marrow samples indicate no differences in ERCC1 gene copy number between high expressors and low expressors [39].

References