Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043346 (xeroderma pigmentosum)
 2,924 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

As DNA repair plays an important role in genetic susceptibility to cancer, assessment of the DNA repair phenotype is critical for molecular epidemiological studies of cancer. In this report, we compared use of the luciferase (luc) reporter gene in a host-cell reactivation (HCR) (LUC) assay of repair of ultraviolet (UV) damage to DNA to use of the chloramphenicol (cat) gene-based HCR (CAT) assay we used previously for case-control studies. We performed both the assays on cryopreserved lymphocytes from 102 healthy non-Hispanic white subjects. There was a close correlation between DNA repair capacity (DRC) as measured by the LUC and CAT assays. Although these two assays had similar variation, the LUC assay was faster and more sensitive. We also analyzed the relationship between DRC and the subjects' previously determined genotypes for four polymorphisms of two nucleotide-excision repair (NER) genes (in intron 9 of xeroderma pigmentosum (XP) C and exons 6, 10 and 23 of XPD) and one polymorphism of a base-excision repair gene in exon 10 of X-ray complementing group 1 (XRCC1). The DRC was significantly lower in subjects homozygous for one or more polymorphisms of the two NER genes than in subjects with other genotypes (P=0.010). In contrast, the polymorphic XRCC1 allele had no significant effect on DRC. These results suggest that the post-UV LUC assay measures NER phenotype and that polymorphisms of XPC and XPD genes modulate DRC. For population studies of the DNA repair phenotype, many samples need to be evaluated, and so the LUC assay has several advantages over the CAT assay: the LUC assay was more sensitive, had less variation, was not radioactive, was easier to perform, and required fewer cryopreserved cells. These features make the LUC-based HCR assay suitable for molecular epidemiological studies.
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PMID:Rapid assessment of repair of ultraviolet DNA damage with a modified host-cell reactivation assay using a luciferase reporter gene and correlation with polymorphisms of DNA repair genes in normal human lymphocytes. 1242 37

DNA repair of bulky adducts is essential for a normal life, as demonstrated by the existence of rare but dramatic diseases, such as xeroderma pigmentosum (XP), associating DNA repair deficiency and a high cancer proneness. It is plausible that small variations in the efficacy of repair in the normal population may facilitate cancer development in exposed individuals. In order to check this hypothesis, associations between single nucleotide polymorphisms (SNPs) in key genes and some frequent human cancers have been researched. Among the repair proteins, the XPD protein is interesting because it is a major player in the nucleotide excision repair pathway and is also involved in transcription initiation and in the control of the cell cycle and apoptosis. Several SNPs have been described in the ERCC2/XPD gene, but three in particular have been studied: the C-->A silent polymorphism (Arg156Arg) in exon 6, the G-->A polymorphism leading to Asp312Asn in exon 10 and the A-->C polymorphism leading to Lys751Gln in exon 23. We review here the epidemiological studies examining whether these polymorphisms are correlated with reduced DNA repair efficiency (analysed using different assays), their influence on the development of cutaneous carcinomas and smoking-related cancers and their possible interactions with environmental exposures.
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PMID:ERCC2/XPD gene polymorphisms and cancer risk. 1243 43

Proteins having DNA helicase activity play very important roles in many processes involving DNA workings such as replication, repair, and recombination. In this decade, many DNA helicase genes have been cloned as the causative genes of human recessive heredity diseases. These are the causative genes for Xeroderma pigmentosum (XPB and XPD), Cockayne syndrome (CSB), diffuse collagen disease (Ku80), alpha-thalassmia (ATR-X), Bloom syndrome (BLM), Werner syndrome (WRN) and Rothmund-Thomson syndrome (RTS). The yeast homologue genes of these human DNA helicase genes exist. S. cerevisiae RAD25/SSL2, RAD3, RAD26, YKU80/HDF2 and RAD54 are the homologue for XPB/ERCC3, XPD/ERCC2, CSB/ERCC6, Ku80/XRCC5 and ATR-X/HX2, respectively. E coli. recQ gene and S. cerevisiae SGS1 are the homologue for all BLM, WRN and RTS. A search of whole genome of S. cerevisiae revealed that SGS1 is the sole homologue of recQ in S. cerevisiae. Thus it seems likely that SGS1 is a functional homologue of one or several human RecQ family genes. Many basic or essential functions are well conserved in the cells from lower eukaryotic to higher mammalian. The functional analysis in yeast could make an useful insight for the human homologue. To clarify the functions of S. cerevisiae Sgs1 and to get an insight into the functions of Blm, Wrn and Rts, in this study, we analyzed the phenotype of sgs1 disruptant and in detail the cause of the poor sporulation phenotype of sgs1 disruptants in relation to meiotic processes including meiotic recombination. The poor sporulation of sgs1 disruptants was complemented with a mutated SGS1 gene encoding a protein lacking DNA helicase activity; however, the mutated gene could suppress neither the sensitivity of sgs1 disruptants to methyl methanesulfonate (MMS) and hydroxyurea nor the mitotic hyperrecombination phenotype of sgs1 disruptants. The N-terminal 1-45 amino acid region and 698-1195 amino acid region of Sgs1, which including helicase domain and C-terminal RecQ conserved region with helicase activity, were required for complementation of MMS sensitivity and suppression of hyperrecombination of sgs1 disruptants in mitotic growth. The 126-400 and 596-1195 amino acid regions of Sgs1 were required for complementation of poor sporulation and of reduced meiotic functions. These regions required for the mitotic or meiotic functions of Sgs1 were well overlapped with the interaction regions of Top3 and Top2. Some of these results might explain the mechanism of the symptom of RecQ-related syndromes.
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PMID:[Functional analysis of yeast homologue gene associated with human DNA helicase causative syndromes]. 1263 84

Mutations in the XPD gene result in xeroderma pigmentosum (XP) and trichothiodystrophy (TTD), the phenotypes of which are often intricate. To understand the genotype/phenotype relationship, we engineered recombinant TFIIHs in which XPD subunits carry amino acid changes found in XPD patients. We demonstrate that all the XPD mutations are detrimental for XPD helicase activity, thus explaining the NER defect. We also show that TFIIH from TTD patients, but not from XP patients, exhibits a significant in vitro basal transcription defect in addition to a reduced intracellular concentration. Moreover, when XPD mutations prevent interaction with the p44 subunit of TFIIH, transactivation directed by certain nuclear receptors is inhibited, regardless of TTD versus XP phenotype, thus explaining the overlapping symptoms. The implications of these mutations are discussed using a structural model of the XPD protein. Our study provides explanations for the nature and the severity of the various clinical features.
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PMID:Basal transcription defect discriminates between xeroderma pigmentosum and trichothiodystrophy in XPD patients. 1282 Sep 75

Gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN) and cisplatin are commonly used in the treatment of many solid tumors, although the impact of chemotherapy is limited in metastatic non-small cell lung cancer. However, in clinical practice, there is a minority of patients who can attain long-term survival. Upregulation of mRNA transcripts has been linked to chemoresistance, and in some instances, mRNA expression has been correlated with polymorphisms. Cisplatin resistance is directly linked to the nucleotide excision repair system, specifically to the transcription-coupled nucleotide excision repair pathway that involves genes that are deficient in rare inborn disorders such as Cockayne syndrome and xeroderma pigmentosum. Overexpression of ERCC1 correlates with poor survival in gemcitabine/cisplatin-treated non-small cell lung cancer patients. At the preclinical level, ERCC1 and XPD mRNA expression correlate with each other, and overexpression of XPD causes selective cisplatin resistance in human tumor cell lines. XPD polymorphisms have been associated with lower DNA repair capacity. In our experience, time to progression is significantly higher in gemcitabine/cisplatin-treated patients with the Lys751Gln genotype (9.6 months) than in those with the Lys751Lys genotype (4.2 months; P =.03). Other polymorphisms involved in parallel DNA repair systems may well provide the same information, indicating a high degree of biologic redundancy. The overexpression of the subunit M1 of ribonucleotide reductase (RRM1) has been linked to gemcitabine resistance in our retrospective assessment. Preliminary findings that a subset of gemcitabine/cisplatin-treated patients with low ERCC1 and RRM1 mRNA levels show a significantly longer survival and highlight the possibilities of individually tailored chemotherapy.
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PMID:Targeted therapy in combination with gemcitabine in non-small cell lung cancer. 1291 17

Xeroderma pigmentosum (XP) and trichothiodystrophy (TTD) are rare heritable diseases. Patients suffering from XP and 50% of TTD afflicted individuals are photosensitive and have a high susceptibility to develop skin tumors. One solution to alleviating symptoms of these diseases is to express the deficient cDNAs in patient cells as a form of gene therapy. XPC and TTD/XPD cell lines were complemented using retroviral transfer. Expressed wild-type XPC or XPD cDNAs in these cells restored the survival to UVC radiation to wild-type levels in the respective complementation groups. Although complemented XP cell lines have been studied for years, data on cyclobutane pyrimidine dimer (CPD) repair in these cells at different levels are sparse. We demonstrate that CPD repair is faster in the complemented lines at the global, gene, strand specific, and nucleotide specific levels than in the original lines. In both XPC and TTD/XPD complemented lines, CPD repair on the non-transcribed strand is faster than that for the MRC5SV line. However, global repair in the complemented cell lines and MRC5SV is still slower than in normal human fibroblasts. Despite the slower global repair rate, in the complemented XPC and TTD/XPD cells, almost all of the CPDs at "hotspots" for mutation in the P53 tumor database are repaired as rapidly as in normal human fibroblasts. Such evaluation of repair at nucleotide resolution in complemented nucleotide excision repair deficient cells presents a crucial way to determine the efficient re-establishment of function needed for successful gene therapy, even when full repair capacity is not restored.
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PMID:Efficient repair of cyclobutane pyrimidine dimers at mutational hot spots is restored in complemented Xeroderma pigmentosum group C and trichothiodystrophy/xeroderma pigmentosum group D cells. 1294 86

Only about one third of non-small-cell lung cancer (NSCLC) patients respond to cisplatin-based chemotherapy. Cisplatin DNA adducts are commonly repaired through the nucleotide excision repair pathway. The study of rare inherited disorders such as xeroderma pigmentosum and Cockayne syndrome has disclosed that XP genes, including XPD, play an essential role in DNA repair, both in the global genomic repair and in the transcription-coupled repair pathways. XPD polymorphism and decreased expression of XP genes have both been linked to lower DNA repair capacity. ERCC1 overexpression has been associated with cisplatin resistance, and experimental evidence shows a close association between ERCC1 and XPD. In the present study, we have examined XPD polymorphisms at codons 751 and 312 in DNA isolated from peripheral blood in 39 patients with gemcitabine/cisplatin-treated locally advanced non-small-cell lung cancer Although no significant correlation was observed between XPD genotype and objective response, a trend toward better response was observed in patients with XPD polymorphism at codon 312. The map of the nucleotide excision repair pathway can be used to design translational research studies to identify and validate predictive markers of response to cisplatin, and the Spanish Lung Cancer Group has recently accrued 250 gemcitabine/cisplatin-treated NSCLC patients for a prospective assessment of XPD genotype
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PMID:Assessment of nucleotide excision repair XPD polymorphisms in the peripheral blood of gemcitabine/cisplatin-treated advanced non-small-cell lung cancer patients. 1462 13

One of the major critical factors for cancer proneness is the cell response to DNA damage. In this work, we used human DNA repair deficient cell lines to investigate the responses to ultraviolet irradiation that lead to apoptosis, and the influence of maintaining the cells resting in confluent state. UV-induced apoptosis is prevented in photolyase-proficient HeLa cells when cyclobutane pyrimidine dimers (CPDs) are removed by photorepair. At the same time, we show recovery of RNA synthesis, thus indicating that blockage of RNA transcription may trigger apoptosis in human cells. On the other hand, confluent primary XPC and trichothiodystrophy (TTD)/XPD cell lines, related to xeroderma pigmentosum and trichothiodystrophy repair syndromes, had a reduced and delayed apoptosis when compared to non-confluent cells. In contrast, XPA cells were similarly sensitive in both the confluent and non-confluent growing state. The effect of cellular confluence on UV-mediated apoptosis in CSB cells, related to Cockayne's syndrome, was unclear. Thus, these results indicate that the induction of apoptosis by UV light may also be affected by DNA replication. In addition, they argue for the use of confluent primary cells in studies of induction of apoptosis by UV, a condition close to skin cells in vivo.
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PMID:Effect of cell confluence on ultraviolet light apoptotic responses in DNA repair deficient cells. 1464 17

Cisplatin or carboplatin is commonly used with gemcitabine, docetaxel, paclitaxel or vinorelbine as chemotherapy doublets in the treatment of advanced non-small cell lung cancer. Several randomized trials have failed to identify major differences in survival between any of these doublets. This lack of evidence for improvement in survival with any chemotherapy regimen has created a tabula rasa in which no more large randomized trials should be conducted with out including a genetic analysis. Patients see survival as their major concern, and other considerations, such as cost of treatment and qualify of life, are relegated to lower positions. Genetic alterations related to the transcription-coupled repair pathway of the nucleotide excision repair system (TC-NER) have revealed the subset of patients who are resistant to cisplatin. TC-NER involves genes that are deficient in rare inborn disorders such as Cockayne syndrome and xeroderma pigmentosum. For a long time, ERCC1 mRNA levels have been known to correlate with DNA repair capacity in various tissues. Levels of DNA cisplatin adducts in peripheral blood and buccal mucosa cells predict chemotherapy response, and high ERCC1 mRNA levels have been related to chemoresistance in ovarian cancer and in malignant lymphocytes from chronic lymphocytic leukemia. Moreover , in some instances, mRNA expression has been correlated with polymorphisms. Overexpression of ERCC1 correlates with poor survival gemcitabine/cisplatin-treated non-small cell lung cancer patients. An ongoing customized ERCC1-based chemotherapy trial has been established on this knowledge. Patients are randomized to the control arm of cisplatin/docetaxel is combined with cisplatin or gemcitabine according to ERCC1 levels. To date, 80 patients have been included. At the preclinical level, ERCC1 and XPD mRNA expression correlate with each other, and overexpression of XPD causes selective cisplatin resistance in human tumor cell lines. Some XPD polymorphisms have been associated with lower DNA repair capacity. In our experience, time to disease progression is significantly higher in gemcitabine/cisplatin-treated patients with the Lys751Gln genotype (9.6 months) than in those with the Lys751Lys genotype (4.2 months; p = 0.03). Other polymorphisms involved in parallel DNA repair systems may well provide the same information, indicating a high degree of biological redundancy. The overexpression of the subunit M1 of ribonucleotide reductase (RRM1) has been linked to gemcitabine resistance in our retrospective assessment. Preliminary findings indicate that a subset of gemcitabine/cisplatin-treated patients with low ERCC1 and RRM1 mRNA levels show a significantly longer survival. This highlights the possibilities of individually tailored chemotherapy. However, in patients treated with cisplatin/vinorelbine, the opposite effect has been observed. Patients with Lys751Lys had a longer time to progression. When docetaxel was added to gemcitabine/cisplatin, patients with Lys751Lys also had better survival. Our findings indicate that TC-NER status can help to decide between cisplatin/gemcitabine and docetaxel/ cisplatin. TC-NER-dependent activity is similar to other anticancer agents that cause DNA-binding enzymes to kill cells (topoisomerase inhibitors). At least 50% of non-small cell lung cancer patients harbor Lys751Lys and can benefit from docetaxel/ cisplatin treatment. Genes involved in spindle formation, centrosome functions and mRNA transport along the microtubule tracks should provide further information on potential markers of docetaxel resistance.
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PMID:Influence of genetic markers on survival in non-small cell lung cancer. 1466 33

We investigated the association of urinary bladder cancer with genetic polymorphisms in the xeroderma pigmentosum complementation group C (XPC), group D (XPD) and group G (XPG), X-ray repair cross-complementing group 1 (XRCC1) and group 3 (XRCC3), Nijmegen breakage syndrome 1 (NBS1), cyclin D1, methylene-tetrahydrofolate reductase (MTHFR), NAD(P)H dehydrogenase quinone 1 (NQO1), H-ras and glutathione S-transferase theta 1 (GSTT1) genes. Bladder cancer patients from the different hospitals in Stockholm County Council area and matching controls were genotyped for different polymorphisms. The frequency of the variant allele for A/C polymorphism in exon 15 of the XPC gene was significantly higher in the bladder cancer cases than in the controls (OR 1.49, 95% CI 1.16-1.92, P = 0.001). The variant allele homozygote genotype for the T/C polymorphism in exon 1 of the H-ras gene was associated with a decreased risk for bladder cancer (OR 0.12, 95% CI 0.02-0.67, P = 0.006). The variant allele genotypes for the single nucleotide polymorphisms (SNPs) in DNA repair genes, XPG and NBS1, showed a marginal association with the occurrence of bladder cancer (OR 0.38, 95% CI 0.15-0.94, P = 0.03 and OR 1.64, 95% CI 0.92-2.90, P = 0.09, respectively). We also report a positive correlation between the null homozygote of GSTT1 with the risk of bladder cancer (OR 2.54, 95% CI 1.32-4.98, P = 0.003). For other polymorphisms included in this study, NBS1 Glu185Gln, XPD Lys751Gln, XPG Asp1104His, XRCC1 Arg399Gln, XRCC3 Thr241Met, cyclin D1 Pro242Pro, MTHFR Ala222Val and Glu429Ala, NQO1 Arg139Trp and Pro187Ser, no significant differences for genotype distributions and allele frequencies between the bladder cancer cases and the controls were observed in the present study.
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PMID:Polymorphisms in DNA repair and metabolic genes in bladder cancer. 1468 16


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