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Query: UMLS:C0043346 (xeroderma pigmentosum)
 2,924 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

DNA damage repair, responsible for maintaining the genome integrity, plays a central role in cancer biology. Individual DNA repair capacity is genetically determined. Inherited defect in nucleotide excision repair (NER) genes leads to three distinct and extremely rare disorders: xeroderma pigmentosum, associated with high risk of skin cancer, Cockayne syndrome, and trichothiodystrophy. The recently identified common polymorphism in several NER genes may also influence a risk of cancer in general population. The review presents current knowledge about a role of genetic variation of NER genes in cancer predisposition.
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PMID:[Repair of DNA damage using nucleotide excision repair (NER)--relationship with cancer risk]. 1241 14

UV light provokes DNA lesions that interfere with replication and transcription. These lesions may compromise cell viability and usually are removed by nucleotide excision repair (NER). In humans, inactivation of NER is associated with three rare autosomal recessive inherited disorders: xeroderma pigmentosum (XP), Cockayne syndrome, and trichothiodystrophy. The NER earliest step is lesion recognition by a complex formed by XPC and HHR23B proteins. In a subsequent step, XPA protein becomes associated to the repair complex. Here we investigate whether XPA and XPC proteins, involved in global genome repair, may contribute to a signal transduction pathway regulating the response to UVC-induced lesions. We monitored the expression of several UVC-induced genes in cells deficient in either a transduction pathway or mutated on an NER gene. Expression of the KIN17 gene is induced after UVC irradiation independently of p53 and of activating transcription factor 2. However, in human cells derived from XPA or XPC patients the UVC-induced accumulation of KIN17 RNA and protein is abolished. Our results indicate that the presence of functional XPA and XPC proteins is essential for the up-regulation of the KIN17 gene after UVC irradiation. They also show that the integrity of global genome repair is required to trigger KIN17 gene expression and probably other UVC-responsive genes.
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PMID:Global genome repair is required to activate KIN17, a UVC-responsive gene involved in DNA replication. 1252 3

Xeroderma pigmentosum, trichothiodystrophy and Cockayne-syndrome are rare, autosomal recessive genodermatoses, which are clinically heterogeneous. Generally, the first signs and symptoms appear at an early age. Although all three syndromes show photosensitivity and an underlying defect in the repair of UV-induced DNA damage, only patients with xeroderma pigmentosum have an increased skin cancer risk. The fact that all three of these syndromes can be caused by mutations in the same gene further emphasizes the role of these syndromes as an important model system for the pathogenesis of skin tumors. Recent findings in the fields of DNA repair, regulation of transcription and immunology have not only further unraveled the underlying mechanisms of these diseases but also provided important insights into the pathogenesis of skin tumors. The clinical characteristics of xeroderma pigmentosum and related DNA repair deficiencies are reviewed with an attempt to point out direct connections between clinical signs and symptoms and their underlying mechanisms.
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PMID:[Xeroderma pigmentosum and related syndromes]. 1256 55

Xeroderma pigmentosum is a rare disorder transmitted in an autosomal recessive manner. Xeroderma pigmentosum is based on a genetic defect in the DNA repair system. This disease manifests in early childhood. Patients with xeroderma pigmentosum have a marked sensitivity to sunlight and develop serious sunburns with onset of poikilodermia in the light-exposed skin. Squamous cell carcinomas, basal cell carcinomas and malignant melanomas already appear in childhood. The majority of patients die before reaching adulthood because of metastases. Genetically, xeroderma pigmentosum is divided into 7 complementation groups (XP-A to XP-G) and the xeroderma pigmentosum variants (XP-V). Diagnostically, assignment to the specific complementation group is made according to the fusioning of xeroderma pigmentosum fibroblasts. Differential diagnosis must distinguish xeroderma pigmentosum from other so-called DNA-repair-deficiency syndromes like the Cockayne Syndrome and trichothiodystrophy. Currently, there are reports of successful application of a topical DNA Repair Enzyme. This is a recombinant liposomal encapsulated T4 endonuclease V, which repairs UV-induced cyclobutan-pyrimidine dimers. In future, causal therapy could be based on gene therapy. The introduction of an intact repair gene which specifically codes the repair protein, could open new possibilities in the treatment of xeroderma pigmentosum.
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PMID:Xeroderma pigmentosum. 1260 73

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

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

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

Xeroderma pigmentosum (XP), Cockayne syndrome (CS) and trichothiodystrophy (TTD) are genetic disorders with very different clinical features, but all associated with defects in nucleotide excision repair. Defects in the XPA or XPC genes confer sensitivity to UV carcinogenesis in both humans and mice, but only XPA(-/-) mice have increased acute responses to UV exposure, whereas XPC(-/-) mice are normal in this respect. Both XPE and XPF proteins have functions separate from their role in NER, but the exact nature of these functions has not yet been established. The CSA and CSB genes responsible for CS are both components of complexes associated with RNA polymerase II and their role is thought to be in assisting polII in dealing with transcription blocks. XPB and XPD proteins are components of transcription factor TFIIH, which is involved in both basal and activated transcription. XPB is part of the core of TFIIH and has a central role in transcription, whereas XPD connects the core to the CAK subcomplex, and can tolerate many different mutations. Subtle differences in the effects of these different mutations on the many activities of TFIIH and on its stability determine the clinical outcomes, which can be XP, TTD, XP with CS, XP with TTD or COFS. Features of single and double mutant mice indicate that the neurological and ageing features associated with these disorders result from the defects in NER in association with the transcriptional deficiencies. Skin tumours in XP patients have mutations characteristic of UV-induction in the ras, p53 and ptch genes, showing that sunlight-induced mutations in these genes are important in carcinogenesis in XP patients.
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PMID:DNA repair-deficient diseases, xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy. 1472 16

A photosensitive form of trichothiodystrophy (TTD) results from mutations in the same XPD gene as the DNA-repair-deficient genetic disorder xeroderma pigmentosum group D (XP-D). Nevertheless, unlike XP, no increase in skin cancers appears in patients with TTD. Although the ability to repair ultraviolet (UV)-induced DNA damage has been examined to explain their cancer-free phenotype, the information accumulated to date is contradictory. In this study, we determined the repair kinetics of cyclobutane pyrimidine dimers (CPD) and (6-4)photoproducts (6-4PP) in three TTD cell strains using an enzyme-linked immunosorbent assay. We found that all three TTD cell strains are deficient in the repair of CPD and of 6-4PP. UV sensitivity correlated well with the severity of repair defects. Moreover, accumulation of repair proteins (XPB and proliferating cell nuclear antigen) at localized DNA damage sites, detected using micropore UV irradiation combined with fluorescent antibody labeling, reflected their DNA repair activity. Importantly, mutations of the XPD gene affected both the recruitment of the TFIIH complex to DNA damage sites and the TFIIH expression. Our results suggest that there is no major difference in the repair defect between TTD and XP-D and that the cancer-free phenotype in TTD is unrelated to a DNA repair defect.
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PMID:Trichothiodystrophy fibroblasts are deficient in the repair of ultraviolet-induced cyclobutane pyrimidine dimers and (6-4)photoproducts. 1500 40

Xeroderma pigmentosum (XP) and trichothiodystrophy (TTD) syndromes are characterized by deficiency in nucleotide excision repair pathway, but with distinguished clinical manifestations. While XP patients exhibit a high frequency of skin cancer, TTD patients are not cancer prone. The relation between lack of DNA repair and their clinical manifestations was investigated through analysis of the transcriptional profile of 12,600 transcripts in two isogenic cell lines with different capabilities of DNA repair. These cell lines result from a stable transfection of the XPB-TTD allele into XP complementation group B fibroblasts, from an XP patient who also have clinical abnormalities corresponding to Cockayne's syndrome (CS). The microarray assays performed under normal growth conditions showed the expression of distinct groups of genes in each cell line. The UVC-transcription modulation of these cells revealed the changes in 869 transcripts. Some of these transcripts had similar modulation pattern in both cells, although with eventually different time patterns for induction or repression. However, some different 'UVC signature' for each cell line was also found, that is, transcripts that were specifically UV regulated depending on the DNA repair status of the cell. These results provide a detailed portrait of expression profiles that may potentially unravel the causes of the different phenotypes of XP/CS and TTD patients.
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PMID:Transcriptional profiles of unirradiated or UV-irradiated human cells expressing either the cancer-prone XPB/CS allele or the noncancer-prone XPB/TTD allele. 1560 84


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