Xeroderma Pigmentosum Complementation Research Articles

XPC Lys939Gln(A/C)基因多态性与胃癌易感性的Meta分析

Objective To explore the association between Xeroderma pigmentosum complementation C group (XPC) Lys939Gln (A/C) gene polymorphism and the susceptibility of gastric cancer. Methods By searching PubMed, Cochrane Library, Elsevier, Springer-Verlag, China National Knowledge Infrastructure, Chinese Biomedical Literature Data, VIP Database and Wanfang Database, all eligible case-control studies published up to September 2015 were selected and the quality of each article was valuated by two reviewers independently according to the inclusion and exclusion criteria. Meta-analysis was performed by using STATA 12.0 software. Odds ratio (OR) and 95% confidence interval (CI) were calculated. The text was estimated for the subgroup analysis, sensitivity analysis and publication bias test. Results A total of 7 case-control studies were included, including 2 336 cases with gastric cancer and 3 502 controls. The Meta-analysis showed that compared with the allele A, the allele C increased the risk of gastric cancer (OR=1.09, 95%CI: 1.01-1.18, Z=2.12, P=0.034); compared to the genotype AA, the homozygous model (CC) and dominant model (CC+ AC) also increased the risk of gastric cancer (CC vs.AA: OR=1.19, 95%CI: 1.00-1.42, Z=2.00, P=0.046; CC+ AC vs.AA: OR=1.12, 95%CI: 1.00-1.25, Z=2.03, P=0.042). The Meta-analysis showed the statistical significance between XPC Lys939Gln (A/C) gene polymorphism and the gastric cancer risk in subgroup of Asian people (C vs.A: OR=1.10, 95%CI: 1.01-1.20, Z=2.28, P=0.023; CC vs.AA: OR=1.21, 95%CI: 1.01-1.46, Z=2.02, P=0.043; CC+ AC vs.AA: OR=1.13, 95%CI: 1.01-1.27, Z=2.11, P=0.035) and the source of community in the control group (C vs.A: OR=1.11, 95%CI: 1.01-1.21, Z=2.25, P=0.024; CC vs.AA: OR=1.23, 95%CI: 1.02-1.50, Z=2.12, P=0.034). Conclusion XPC Lys939Gln(A/C) gene polymorphism may be associated with the susceptibility of gastric cancer, and genotype CC, CC+ AC and allele C can increase the risk of gastric cancer. Key words: Stomach neoplasms; Polymorphism, genetic; Polymorphism, single nucleotide; Meta-analysis; Xeroderma pigmentosum complementation C group

2,2,4-Triamino-5(2H)-oxazolone is a weak substrate for nucleotide excision repair

Objective: 2,2,4-Triamino-5(2H)-oxazolone (Oz) is a guanine lesion produced by reactive oxygen radicals and photosensitized oxidation. This nucleobase is a potentially mutagenic lesion, and is removed by several base excision repair enzymes. Our purpose is to analyze whether Oz is the substrate of nucleotide excision repair (NER). Materials and Methods: A lymphoblastoid cell line from the patient with xeroderma pigmentosum (XP) complementation group C (XP3BE) was used. Cell-free NER reactions with covalently closed circular DNAs containing the Oz lesion were performed using the XP3BE whole cell extracts with or without the XPC-RAD23B complex. In addition, DNA fragments (180 bp in length) containing the Oz lesion were used for binding reactions with the XPC-RAD23B complex. Results: We analyzed the cell-free NER activity on Oz and the binding affinity of XPC-RAD23B, which initiates NER. Human cell-free NER activity on Oz was detected, though the reactivity to Oz was lower than that on ultra violet (UV)-induced pyrimidine (6-4) pyrimidone photoproduct (6-4PP). Also, binding of XPC-RAD23B with Oz was lower than that with 6-4PP. Conclusion: Because of the low binding affinity of Oz for XPC-RAD23B, NER efficiency on Oz is very low. Therefore, general NER is not the appropriate repair system for Oz.

Xeroderma pigmentosum genes and melanoma risk

Xeroderma pigmentosum is a rare autosomal recessive disease that is associated with a severe deficiency in nucleotide excision repair. The presence of a distinct the nucleotide excision repair (NER) mutation signature in melanoma suggests that perturbations in this critical repair process are likely to be involved with disease risk. We hypothesized that persons with polymorphic NER gene(s) are likely to have reduced NER activity and are consequently at an increased risk of melanoma development. We assessed the association between 94 SNPs within seven XP genes (XPA-XPG) and the melanoma risk in the Polish population. We genotyped 714 unselected melanoma patients and 1,841 healthy adults to determine if there were any polymorphisms differentially represented in the disease group. We found that a significantly decreased risk of melanoma was associated with the Xeroderma pigmentosum complementation (XPC) rs2228000_CT genotype (odds ratio [OR] = 0.15; p < 0.001) and the rs2228000_TT genotype (OR = 0.11; p < 0.001) compared to the reference genotype. Haplotype analysis within XPC revealed the rs2228001_A + G1475A_G + G2061A_A + rs2228000_T + rs3731062_C haplotype (OR = 0.26; p < 0.05) was associated with a significantly decreased disease risk. The haplotype analysis within the Xeroderma pigmentosum group D (XPD) showed a modest association between two haplotypes and a decrease in melanoma risk. There were no major differences between the prevalence of the XP polymorphisms among young or older patients with melanoma. Linkage disequilibrium of XPC: rs2228001, G1475A, G2061A, rs2228000 and rs3731062 was found. The data from our study support the notion that only XPC and XPD genes are associated with melanoma susceptibility.

Abstract 2986: Melanocytes are deficient in repair of oxidative DNA damage and UVC induced photoproducts

Abstract Melanomas occur mainly in sunlight-exposed skin, xeroderma pigmentosum complementation (XP) patients, defective in nucleotide excision repair function, have 1000-fold higher incidence of melanoma. These findings indicate that sunlight induced “bulky” photoproducts are responsible for melanomagenesis. On the other hand, sunlight also induces a high level of reactive oxygen species (ROS) in melanoctes (MC), oxidative DNA damage (ODD) therefore may contribute to melanomagenesis and that the XP protein may participate in ODD repair. To address these questions we determined: 1) the effect of melanin on UVA (320-400 nm) irradiation induced ODD and UV photoproducts using formamidopyrimidine glycosylase (Fpg) and UvrABC incision assays, 2) the repair capacity for ODD and UV-induced photoproducts in MC and XPA cells using host cell reactivation and in vitro DNA repair synthesis assays. We found: 1) UVA irradiation-inducing a significantly higher amount of Fpg sensitive ODD in MC than in normal human skin fibroblasts (NHSF). In contrast, UVA irradiation induces an insignificant amount of UvrABC sensitive sites in either of these two types of cells. 2) Compared to NHSF, MC have a reduced repair capacity for ODD and photoproducts. 3) H2O2 modified DNA induces a higher mutation frequency in MC than in NHSF. 4) XPA cells are deficient in ODD repair and ODD induces a higher mutation frequency in XPA cells than in NHSF. Based on these results, we propose: 1) UVA is a major etiological agent for melanomagenesis and the mechanism is through melanin sensitizes UVA in induction of ODD and reduced repair capacity in MC; 2) the reduced repair capacity for ODD contributes to the high melanoma incidence in XPA patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2986.

Enhancement of XPG mRNA transcription by human interferon-beta in Cockayne syndrome cells with complementation group B.

Human interferon-beta (HuIFN-beta) confers UV-refractoriness in association with increased DNA repair capacity to human cells. We examined the modulation of XPG gene expression by HuIFN-beta in UV-sensitive cells from Cockayne syndrome complementation B (CSB), xeroderma pigmentosum complementation A (XPA) and normal control cells. Northern blot analysis revealed that XPG mRNA was more extensively transcribed in CSB cells treated with HuIFN-beta than in those without HuIFN-beta treatment. XPG mRNA from XPA cells and normal control cells was not markedly transcribed by HuIFN-beta treatment compared to that from CSB cells. The findings suggested that different mechanisms of UV-refractoriness by HuIFN-beta exist between CS and XP.

Host cell reactivation of cisplatin-treated adenovirus is reduced in nucleotide excision repair deficient mammalian cells and several human tumour cells

Cisplatin is widely used for chemotherapy of a variety of human cancers. Cisplatin exerts its toxic effect by covalently binding to DNA, resulting in monofunctional adducts, intrastrand crosslinks, and interstrand crosslinks. Several recent reports suggest that the cellular capacity for DNA repair, especially nucleotide excision repair (NER), is an important determinant in the sensitivity of cells to cisplatin. We have used a sensitive host cell reactivation (HCR) technique to examine the repair capacity for cisplatin-damaged DNA in several different mammalian cell types. HCR of cisplatin-damaged adenovirus (Ad) was reduced in all UV-sensitive NER deficient Chinese hamster ovary (CHO) cells examined (complementation groups 1 to 6) compared to NER proficient CHO cells. HCR of cisplatin-damaged Ad was also reduced in fibroblasts from patients with xeroderma pigmentosum (XP) complementation groups A, B, C, D, F, and G compared to that in normal human fibroblasts. Differences in the HCR of cisplatin-treated Ad were also detected among human cancer cell lines, suggesting some tumour cells may be deficient in the NER of cisplatin-DNA adducts.

Reply to letter by J. H. Robbins

We are grateful to Dr. Robbins for his comments on our recent paper (Johnson et al. 1989), and for bringing to our attention reports of the complete complementation of unscheduled DNA synthesis (UDS) in heterokaryons formed between fibroblasts from xeroderma pigmentosum (XP) complementation group H (XPH) and other XP complementation groups. We regret our previous ignorance of these data (Fujiwara and Satoh 1985; Mamada et al. 1988; Ichihashi et al. 1988) and should have quoted them. As Dr. Robbins points out in his letter, the original report (Moshell et al. 1983) lacked quantitative data on complementation of UDS between XPH and XPD fibroblasts. They did, however, show that complementation for UDS between XPB and XPH cells was less than complete. We cannot explain why the levels of UDS achieved in hybrids between HD2 and different fibroblasts, especially from groups E and F, should appear relatively low, but we state clearly that a degree of complementation is expressed in these cases, as it is when the partner is XPH or XPD. It is also important to reiterate that the UDS levels we see are those in hybrid nuclei, not in the independent nuclei of recent heterokaryon constructs. There is very considerable variation in the capacity for UDS among the different XPD mutations (Robbins et al. 1974; Pawsey et al. 1979; Paterson 1982; Fischer et al. 1982). In no case that we know of is this variation associated with significant removal of photoproducts (Zelle and Lohmann 1979; Paterson 1982; Mitchell 1988). To rely on UDS as a single diagnostic measure of an XPD mutation could be hazardous. The availability of a permanent repair-defective cell line permits backcrosses to be made to the parental and other mutant cells. Hybrids so derived can be tested for the expression of complementation much more extensively than by the shortterm assay of UDS alone. In particular, hybrids allow the restoration of viability to be assessed. At the risk of tedium we reiterate that UDS is a single and possibly misleading assay for competence in nucleotide excision repair, and we suggest that future studies of complementation are likely to include a more wide-ranging assessment of repair restitution in XP crosses. The availability of immortal cell lines from most of the XP complementation groups will make this task possible and probably obligatory. It is always difficult, and rightly so, to provide sufficient evidence to convince sceptics about a negative finding. Direct evidence for the suspected XPD and XPH identity, based on molecular probes for the XPD gene (Arrand et al. 1989), will hopefully soon be available. However, until then, evidence obtained from somatic cell hybrids between XPD and XPH cell lines will have to suffice.

The response to DNA damage induced by 4-nitroquinoline-1-oxide or its 3-methyl derivative in xeroderma pigmentosum fibroblasts belonging to different complementation groups: evidence for different epistasis groups involved in the repair of large adducts in human DNA.

The data in this paper show that when the inhibition of growth is measured, xeroderma pigmentosum (XP) complementation groups A, G and D are very sensitive to 4-nitroquinoline-1-oxide (4NQO), whereas only XP groups G and D are very sensitive to 3-methyl-4NQO (3me4NQO). Cells belonging to XP-C group are not particularly sensitive to either agent. Thus there are different epistasis groups for the excision repair of DNA adducts induced by these agents as opposed to the repair of u.v. damage. DNA polymerase alpha is involved in the repair of 4NQO-induced lesions because aphidicolin blocks their repair. XP cells from all the above groups are defective to some extent in this repair. The degree of repair defectiveness follows that seen after u.v., with even the XP-C cell line used having reduced repair (despite the fact that the inhibition of growth by 4NQO in this cell line was not markedly different from normal). Aphidicolin did not induce breaks in the normal or XP cell lines exposed to 3me4NQO, thus the repair of lesions induced by 3me4NQO does not involve DNA polymerase alpha in any of the cell lines. Finally, catalase reduces the alkaline labile lesions induced by 4NQO, but not 3me4NQO, suggesting the latter agent does not induce substantial amounts of DNA damage by the generation of radicals.

Apurinic DNA endonuclease activities in repair-deficient human cell lines.

Several autosomal recessive diseases are associated with apparent DNA repair defects in cell culture. It seemed likely that a defect in excision repair reported for ataxia telangiectasia cells might reflect a lack of apurinic endonuclease activity. We report here normal levels of apurinic endonuclease activity in extracts of cell lines derived from patients with ataxia telangiectasia, xeroderma pigmentosum (complementation group D), Cockayne dwarfism, Fanconi anemia and Bloom syndrome.