Disease relevance of ERCC6

• Allelic loss of 10q is a common genetic event in malignant gliomas, with three 10q tumor suppressor genes, ERCC6, PTEN, and DMBT1, putatively implicated in the most common type of malignant glioma, glioblastoma [1].
• Proteins encoded by the mfd gene in E. coli and by the ERCC6/CSB gene in humans, both of which possess the so-called helicase motifs, are required for the coupling reaction [2].
• In this study we overproduced the human CSB protein using the baculovirus vector and purified and characterized the recombinant protein [2].
• Additionally we have examined interactions between TFIIH components, the human NER protein XPG, and the CSB protein which is implicated in Cockayne syndrome (CS) [3].
• Higher mRNA levels of Xeroderma pigmentosum group B (XPB), which links DNA repair with DNA transcription, and of Cockayne's syndrome group B (CSB), which is essential for gene-specific repair, were observed in tumor tissues that were clinically resistant to platinum-based chemotherapy, as compared with tissues from patients responding to therapy [4].

High impact information on ERCC6

• Finally, there are indications that the genes CSA and CSB, which are implicated in the human hereditary disease Cockayne syndrome, may have a role in transcription [5].
• CSB-deficient mice exhibit all of the CS repair characteristics: ultraviolet (UV) sensitivity, inactivation of transcription-coupled repair, unaffected global genome repair, and inability to resume RNA synthesis after UV exposure [6].
• In contrast to the human syndrome, CSB-deficient mice show increased susceptibility to skin cancer [6].
• These observations suggest that the products of the CSA and CSB genes are involved in transcription [7].
• Moreover, studies of cells deficient in XPC or in the genes implicated in Cockayne syndrome (CSA and CSB) indicated that the drug sensitivity is specifically dependent on the transcription-coupled pathway of NER [8].

Chemical compound and disease context of ERCC6

• In the present study we characterized phosphorothioate backbone antisense oligodeoxynucleotides (AOs) that reduced the levels of CSB mRNA in A2780/CP70 ovarian carcinoma cells [9].
• Finally, CSB(-/-) but not CSA(-/-) mice fed with food containing di(2-ethylhexyl)phthalate (causing elevated levels of oxidative DNA damage in the liver) show weight reduction [10].
• We have previously reported that the Cockayne syndrome group B gene product (CSB) contributes to base excision repair (BER) of 8-hydroxyguanine (8-OH-Gua) and the importance of motifs V and VI of the putative helicase domains of CSB in BER of 8-OH-Gua [11].

Biological context of ERCC6

• Structure and expression of the excision repair gene ERCC6, involved in the human disorder Cockayne's syndrome group B [12].
• Analysis of ERCC6 cDNA clones revealed the occurrence of alternative polyadenylation, resulting in the (differential) expression of two mRNA molecules (which are barely detectable on Northern blots) of 5 and 7 kb in length [12].
• An RFLP detected within the ERCC6 locus can be helpful in linkage analysis [13].
• Localization of the nucleotide excision repair gene ERCC6 to human chromosome 10q11-q21 [13].
• In all patient groups, when expression was low for ERCC1, expression was also low for ERCC2 and ERCC6, suggesting that expression of these genes may be coordinated within an individual although they are located on two different chromosomes [14].

Anatomical context of ERCC6

• The human CSB (ERCC6) gene corrects the transcription-coupled repair defect in the CHO cell mutant UV61 [15].
• 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 [14].
• Since transcription of the JUN gene was UV-induced in all fibroblast strains, including CSB, the defective repair of the transcribed strand in CSB cannot be explained by a lack of transcription; rather, it appears to be a true DNA repair defect [16].
• Furthermore, we find that CSB-deficient cell lines are hypersensitive to inhibition of PARP [17].
• Enhanced ERCC6 expression was observed in lymphocytes from healthy donors bearing ERCC6 C-6530>G alleles [18].

Associations of ERCC6 with chemical compounds

• When we stratified the patients according to intravesical Bacillus Calmette-Guerin treatment, we found a significant trend for shorter recurrence-free survival time in patients with variant alleles of XPA or ERCC6 polymorphisms who received Bacillus Calmette-Guerin treatment (log rank test, P = 0.078 and 0.022, respectively) [19].
• Melatonin further and statistical significantly up-regulated ERCC6 mRNA expression in the peri-ischemic region of rat brains [20].
• We previously reported that the CSB protein is involved in cellular repair of 8-hydroxyguanine, an abundant lesion in oxidatively damaged DNA and that the putative helicase motif V/VI of the CSB may play a role in this process [21].
• The present study investigated the role of the CSB protein in cellular repair of 8-hydroxyadenine (8-OH-Ade), another abundant lesion in oxidatively damaged DNA [21].
• By site-directed mutagenesis the invariant lysine residue in the NTP-binding motif of CSB was substituted with a physicochemically related arginine [22].

Physical interactions of ERCC6

• XPG binds transcription-sized DNA bubbles through two domains not required for incision and functionally interacts with CSB on these bubbles to stimulate its ATPase activity [23].

Regulatory relationships of ERCC6

• Activation of p53 would inhibit CSB, stalling transcription complexes and locally blocking chromatin condensation [24].

Other interactions of ERCC6

• Together, these results implicate coordinated recognition of stalled transcription by XPG and CSB in TCR initiation and suggest that TFIIH-dependent remodeling of stalled RNAPII without release may be sufficient to allow repair [23].
• Deletion mapping demonstrated 10q loss in 14 of 67 informative cases, with the PTEN and DMBT1 regions involved in all deletions but with the ERCC6 locus spared in two cases [1].
• Here we have extended these studies to compare low-grade tumors to high-grade tumors and to include ERCC3 (which links DNA repair with DNA transcription) and ERCC6 (which is essential for gene-specific repair) [25].
• CSB cells exhibited rapid repair near the transcription initiation site but were deficient in repair of sequences encountered by RNA polymerase during elongation (beginning at position +20) [16].
• Bioinformatics indicated a putative binding-element alteration on the sequence containing C-6530>G SNP in the 5' flanking region of ERCC6 from Sp1 on the C allele to SP1, GATA-1, and OCT-1 on the G allele [18].

Analytical, diagnostic and therapeutic context of ERCC6

• Double labeling showed that ERCC6 only co-localized with proliferating cell nuclear antigen (PCNA), a member of the nuclear excision repair complex, but not with TUNEL [20].
• Molecular cloning of the human DNA excision repair gene ERCC-6 [26].
• These data, together with fluorescence in situ hybridization analysis, demonstrated that the two siblings with XP as well as the CS patient were homozygous for the same CSB mutated allele, containing a silent C2830T change and a nonsense mutation C2282T converting Arg735 to a stop codon [27].
• We analyzed the CSB.DNA complex by scanning force microscopy and measured a shortening of DNA contour length upon CSB binding in the presence of ATP [28].
• Chemically modified (<mixed backbone>) AOs (MBOs) targeting CSB were able to potentiate the anti-tumor effect of cisplatin against A2780/CP70 tumor xenografts formed in nude mice [9].

References