Disease relevance of ERCC2

• Two of them, ERCC2 and ERCC3, are responsible for atypical forms of XP disorders which confer a high predisposition to skin cancer [1].
• To narrow the location of this tumor suppressor further, we studied 138 gliomas for loss of allelic heterozygosity at six microsatellite polymorphisms between APOC2 and HRC, including a newly described polymorphism in the ERCC2 gene [2].
• On Cox multivariate analysis, significant associations with toxicity were found for LIG4 (T>C, Asp(568)Asp), ERCC2 (G>A, Asp(711)Asp), CYP2D6*4 (G>A, splicing defect), mean bladder dose >60 Gy, and dose to 30% of rectal volume >75 Gy [3].
• Moreover, one haplotype in ERCC2 was associated with a decreased risk of lung cancer (OR = 0.40, 95% CI 0.19-0.85) compared to the most common haplotype [4].
• In this review, the authors focused on the x-ray repair cross-complementing protein group 3 (XRCC3) and xeroderma pigmentosum group D (XPD)/excision repair cross-complementing rodent repair deficiency (ERCC2) genes, because they are among the most extensively studied but no final conclusion has yet been drawn about their role in cancer occurrence [5].

Psychiatry related information on ERCC2

• The p44 subunit plays a crucial role in the overall activity of the transcription/DNA repair factor TFIIH: on the one hand its N-terminal domain interacts with and regulates the XPD helicase (, ); on the other hand, as shown in the present study, it participates with the promoter escape reaction [6].
• The influence of the XPA-A23A genotype was not evident in this statistical analysis, and no associations with XPD polymorphisms, dietary habits or tobacco smoking were found [7].
• Besides XP, mutations in XPD can cause another seemingly unrelated syndrome, trichothiodystrophy (TTD), characterized by sulfur-deficient brittle hair, ichthyosis, and physical and mental retardation [8].
• The mean TTD was 13.8 +/- 10.8 months and did not differ by gender, household composition, or type of dementia [9].
• The brothers were divided into more (MAG) and less active groups according to physical activity and fitness [10].

High impact information on ERCC2

• DNA repair-deficient trichothiodystrophy (TTD) results from mutations in the XPD and XPB subunits of the DNA repair and transcription factor TFIIH [11].
• We demonstrate that the XPD mutation alters cdk7 function in RARalpha phosphorylation [12].
• Inherited mutations in the XPD subunit of the general transcription/repair factor TFIIH yield the rare genetic disorder Xeroderma pigmentosum (XP), the phenotypes of which cannot be explained solely on the basis of a DNA repair defect [12].
• XPD mutations prevent TFIIH-dependent transactivation by nuclear receptors and phosphorylation of RARalpha [12].
• Transactivation is restored upon overexpression of either the wild-type XPD or the RARalphaS77E (a mutation which mimics phosphorylated RARalpha) [12].

Chemical compound and disease context of ERCC2

• Patients were ascertained from nine geographic regions in Australia, Canada, Italy and the United States. Positive associations were observed for XPD 312 Asn/Asn versus Asp/Asp [odds ratio (OR) = 1.5, 95% confidence interval (CI) 1.2-1.9] and XPD 751 Gln/Gln versus Lys/Lys (OR = 1.4, 95% CI 1.1-1.7) genotypes and melanoma [13].
• Our results indicate that XPD overexpression in SK-MG-4 cells leads to cisplatin resistance without affecting the nucleotide excision repair activity or UV light sensitivity of the cell [14].
• We investigated the possible association of ERCC2 codon 751 A-->C polymorphism (lysine to glutamine) with arsenic-induced hyperkeratosis and correlated ERCC2 genotypes with increased frequencies of chromosomal aberration to ascertain whether any genotype leads to sub-optimal DNA repair [15].
• CONCLUSION: The present data provided evidences and confirmed the authors' previous results that ERCC2 contributes, at least partially, to alkylating agent resistance in human glioma cell line [16].
• The pcDNA3-ERCC2 was transfected into a selected ERCC2 negative human glioma cell line, SKMG-4, using liposome-mediated transfection [16].

Biological context of ERCC2

• The ERCC2/DNA repair protein is associated with the class II BTF2/TFIIH transcription factor [1].
• A long-range restriction map of the human chromosome 19q13 region: close physical linkage between CKMM and the ERCC1 and ERCC2 genes [17].
• We demonstrated previously that DRC for removal of benzo[a]pyrene diol epoxide-induced DNA damage measured by a host-cell reactivation assay was modulated by two XPD/ERCC2 polymorphisms in lung cancer [18].
• Three linked SNPs in ERCC2 were associated with lung cancer with similar ORs; e.g., persons with the Gln allele at codon 751 had a 60% reduction of lung cancer (OR = 0.40, 95% CI 0.18-0.89) [4].
• The second gene is telomeric (in the human) to ERCC2 and contains a motif found in ankyrins, some cell cycle proteins, and transcription factors [19].

Anatomical context of ERCC2

• The patterns of expression of 3 human DNA-repair genes (ERCC1, ERCC2, ERCC6) were assessed in 52 bone-marrow specimens obtained from cancer patients prepared for autologous bone-marrow transplantation [20].
• Associations between XRCC1 and ERCC2 polymorphisms and DNA damage in peripheral blood lymphocyte among coke oven workers [21].
• DNA repair-deficient XPB and XPD mutant cell lines exhibited an increase in transduction efficiency by both HIV- and Moloney murine leukemia virus-based retroviral vectors [22].
• Transcriptional regulation of the TFIIH transcription repair components XPB and XPD by the hepatitis B virus x protein in liver cells and transgenic liver tissue [23].
• The human cell lines, defective in nucleotide excision protein, such as xeroderma pigmentosum (XP) A, XPD, and XPG, excised Ultraviolet C-induced adducts less rapidly than normal fibroblasts, but excised As(2)O(3) adducts at the same rate as the normal cells [24].

Associations of ERCC2 with chemical compounds

• XPD/ERCC2 is a helicase involved in the nucleotide excision repair pathway, which recognizes and repairs many structurally unrelated lesions, such as bulky adducts and thymidine dimers [5].
• We have evaluated host cell reactivation and cell survival of wild type Chinese hamster ovary cells and of mutants in the NER-genes ERCC1, ERCC2, and ERCC4 after treatment with the methylating compounds dimethylsulfate and methylnitrosourea [25].
• RESULTS: The rank ordering of sensitivity to both 4HC and PM, based on the combined survival data, was UV41/UV4/UV20 > > UV61/UV24/UV135/EM9 > or = UV5 approximately AA8 [26].
• Protein expression was also compared with a pre-defined categorisation of the standard agents into six mechanism-of-action (MOA) groups resulting in an inverse association between XPD and alkylating agent sensitivity [27].
• In 42 healthy Japanese non-smoking men, we investigated the relationship between the MN frequency levels and genetic polymorphisms in three different genes: aldehyde dehydrogenase 2 (ALDH2), X-ray repair cross-complementing group 1 (XRCC1) and excision repair cross-complementing group 2 (ERCC2) [28].

Physical interactions of ERCC2

• Isolation and characterization of two human transcription factor IIH (TFIIH)-related complexes: ERCC2/CAK and TFIIH [29].

Regulatory relationships of ERCC2

• Furthermore, we show that gammaH2Ax, DSBs, and RAD51 foci are synergistically induced in EM9 cells with camptothecin, suggesting that lack of SSB repair in EM9 causes more collapsed forks and more recombination repair [30].
• We have investigated both DNA ligase activities and a protein which stimulates DNA ligase activity in mutant EM9 cells, XRCC1-transfectant H9T3-7-1 cells and wild-type AA8 cells [31].

Other interactions of ERCC2

• This deficiency can be rescued by transferring the wild-type XPB or XPD gene into the corresponding mutant cells [32].
• This TFIIH*-dependent transcription reaction was stimulated by ERCC2/CAK [29].
• In this report, we investigated the association between the repair phenotype of ultraviolet (UV)-induced damage and genotypes of three DNA repair genes, XPC and XPD [involved in nucleotide excision repair (NER)] and XRCC1 [involved in base excision repair (BER)] [18].
• Lack of the biotransformation gene GSTM1 and short telomeres were associated with OR = 6.5 (95% CI 2.4-18), whereas homozygous carriers of 312Asn in the DNA repair gene XPD, with short telomeres, displayed an OR of 17 (95% CI 1.9-150) [33].
• Our findings suggest that Ki-ras and ERCC2 SNPs are possible markers for meningioma formation, whereas cyclin D1 and p16 SNPs may be markers of genes that have an inverse effect on the risk to develop meningioma in irradiated and nonirradiated populations [34].

Analytical, diagnostic and therapeutic context of ERCC2

• In this case-control study of 1,010 incident lung cancer cases and 1,011 age and sex frequency-matched cancer-free controls in a Chinese population, we genotyped eight tagging polymorphisms of ERCC2 and ERCC3 using the high-throughput Taqman platform to determine their associations with risk of lung cancer [35].
• The authors identified a sufficient number of epidemiologic studies on cancer to perform meta-analyses for XPD/ERCC2 variants in codons 156, 312, and 751 and XRCC3 variants in codon 241 [5].
• Sequence analysis of the ERCC2 gene regions in human, mouse, and hamster reveals three linked genes [19].
• In the second analysis, DNAs from an independent hybrid panel were digested with restriction enzymes and analyzed by Southern blot hybridization using DNA probes for the three DNA repair genes that are located on human chromosome 19: ERCC1, ERCC2, and X-Ray Repair Cross Complementing 1 (XRCC1) [36].
• In this study, alkaline comet assay was used to detect the DNA damage in peripheral blood lymphocytes among 143 coke-oven workers and 50 non-coke-oven workers, and the effects of genetic polymorphisms of XRCC1 and ERCC2 genes on DNA damage were evaluated [21].

References