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)

Xeroderma pigmentosum (XP) is a human repair-deficient disorder that is caused by mutations in any of eight genes (A-G, V). The genes for complementation groups A-G have been cloned fully or in part, but the gene for the XP variant (XPV) has yet to be cloned. The lack of progress with XPV is in large part due to the rarity of stably transformed cell lines. We have attempted to immortalize fibroblasts from several XPV patients to obtain cell lines with which to characterize this disease and clone the appropriate gene. We have found, as have other investigators, that this XP group is very difficult to immortalize. We used a variety of approaches, including transfection with pSV ori- (a plasmid containing the simian virus (SV) 40 large T antigen) followed by spontaneous transformation, which provided stable immortal lines from Cockayne syndrome A and B, but not from XPV; transfection with pSV ori- and exposure to 3 Gy of X-rays; transfection with pSV ori-, exposure to 2 Gy of X-rays, and treatment with 1 mM ethyl methanesulfonate; transfection with human papilloma virus-16; and infection with SV40. Even though we used as many as 2 x 10(8) cells in some experiments, we were able to immortalize only one of our lines, XP30RO. Because the biochemical defect in XPV cell lines involves the capacity to replicate damaged DNA templates, perhaps the XPV gene product could be a replication factor that interacts with SV40 T antigen, and whose absence from XPV cell lines presents difficulties for the immortalization process to proceed.
Mutat Res 1995 Sep
PMID:Xeroderma pigmentosum variant cells are resistant to immortalization. 756 59

Human replication protein A (RPA; also known as human single-stranded DNA binding protein, or HSSB) is a multisubunit complex involved in both DNA replication and repair. While the role of RPA in replication has been well studied, its function in repair is less clear, although it is known to be involved in the early stages of the repair process. We found that RPA interacts with xeroderma pigmentosum group A complementing protein (XPAC), a protein that specifically recognizes UV-damaged DNA. We examined the effect of this XPAC-RPA interaction on in vitro simian virus 40 (SV40) DNA replication catalyzed by the monopolymerase system. XPAC inhibited SV40 DNA replication in vitro, and this inhibition was reversed by the addition of RPA but not by the addition of DNA polymerase alpha-primase complex, SV40 large tumor antigen, or topoisomerase I. This inhibition did not result from an interaction between XPAC and single-stranded DNA (ssDNA), or from competition between RPA and XPAC for DNA binding, because XPAC does not show any ssDNA binding activity and, in fact, stimulates RPA's ssDNA binding activity. Furthermore, XPAC inhibited DNA polymerase alpha activity in the presence of RPA but not in RPA's absence. These results suggest that the inhibitory effect of XPAC on DNA replication probably occurs through its interaction with RPA.
J Biol Chem 1995 Sep 15
PMID:Human xeroderma pigmentosum group A protein interacts with human replication protein A and inhibits DNA replication. 766 1

Mutations in the p53 gene were analyzed in 23 squamous cell carcinomas (SCCs) and five basal cell carcinomas from 10 xeroderma pigmentosum patients in Tunisia. Fourteen mutations were detected. Most occurred at the dipyrimidine sequences of DNA, suggesting that they were caused by ultraviolet light. A strong correlation was noted between the presence of the p53 mutations and clinical characteristics such as histology and growth of SCC. In well-differentiated grade 1 SCCs, three (27.3%) of 11 tumors had the p53 gene mutations, whereas in grade 2 and grade 3 SCCs, six (85.7%) of seven tumors had the p53 gene mutations (p < 0.05). Tumors less than 8.0 mm in diameter showed a relatively low frequency of mutation (two of 10 tumors, 20.0%), whereas most of the tumors larger than 8.1 mm (seven of eight tumors, 87.5%) had mutations of the p53 gene (p < 0.025). Multiple tumors in the same xeroderma pigmentosum patients also showed this relation. These results suggest that mutations in the p53 gene lead to the invasive and rapid-growing character of SCC.
J Invest Dermatol 1995 Sep
PMID:High prevalence of mutations in the p53 gene in poorly differentiated squamous cell carcinomas in xeroderma pigmentosum patients. 766 20

Xeroderma pigmentosum (XP) is a human hereditary disease characterized by a defect in DNA repair after exposure to ultraviolet light. Among the seven groups of XP, group A (XP-A) patients show the most severe deficiency in excision repair and a wide variety of cutaneous and neurological disorders. We have cloned homologs of the human XPA gene from chicken, Xenopus, and Drosophila, and sequence analysis revealed that these genes are highly conserved throughout evolution. Here, we report characterization of the Drosophila homolog of the human XPA gene (Dxpa). The Dxpa gene product shows DNA repair activities in an in vitro repair system, and Dxpa cDNA has been shown to complement a mutant allele of human XP-A cells by transfection. Polytene chromosome in situ hybridization mapped Dxpa to 3F6-8 on the X chromosome, where no mutant defective in excision repair was reported. Northern blot analysis showed that the gene is continuously expressed in all stages of fly development. Interestingly, the Dxpa protein is strongly expressed in the central nervous system and muscles as revealed by immunohistochemical analysis using anti-Dxpa antibodies, consistent with the results obtained in transgenic flies expressing a Dxpa-beta-galactosidase fusion gene driven by the Dxpa promoter.
J Biol Chem 1995 Sep 22
PMID:Expression and functional analyses of the Dxpa gene, the Drosophila homolog of the human excision repair gene XPA. 767 33

Compromise of genetic information by mutation may result in the dysregulation of cellular growth control and subsequent tumour formation. Xeroderma pigmentosum (XP) is a rare autosomal disease characterized by hypersensitivity of the skin to sunlight and > 1,000-fold increased risk of skin cancers in sun-exposed parts of the body. Cell fusion studies have revealed eight complementation groups in XP (A-G, and an XP-variant form); group C is one of the most common forms of the disease. We have isolated a mouse homologue of the human gene for XP group C and generated XPC-deficient mice by using embryonic stem cell technology. Mice homozygous for the XPC mutant allele (xpcm1/xpcm1) are viable and do not exhibit an increased susceptibility to spontaneous tumour generation at one year of age. However, xpcm1/xpcm1 mice were found to be highly susceptible to ultraviolet-induced carcinogenesis compared with mice heterozygous for the mutant allele (xpcm1/+) and wild-type controls. Homozygous xpcm1 mutant mice also display a spectrum of ultraviolet-exposure-related pathological skin and eye changes consistent with the human disease xeroderma pigmentosum group C.
Nature 1995 Sep 14
PMID:High susceptibility to ultraviolet-induced carcinogenesis in mice lacking XPC. 767 84

Xeroderma pigmentosum (XP) is an autosomal recessive disorder characterized by a high frequency of skin cancer on sun-exposed areas, and neurological complications. XP has a defect in the early step(s) of nucleotide-excision repair (NER) and consists of eight different genetic complementation groups (groups A-G and a variant). We established XPA (group-A XP) gene-deficient mice by gene targeting of mouse embryonic stem (ES) cells. The XPA-deficient mice showed neither obvious physical abnormalities nor pathological alterations, but were defective in NER and highly susceptible to ultraviolet-B- or 9,10-dimethyl-1,2-benz[a]anthracene-induced skin carcinogenesis. These findings provide in vivo evidence that the XPA protein protects mice from carcinogenesis initiated by ultraviolet or chemical carcinogen. The XPA-deficient mice may provide a good in vivo model to study the high incidence of skin carcinogenesis in group A XP patients.
Nature 1995 Sep 14
PMID:High incidence of ultraviolet-B-or chemical-carcinogen-induced skin tumours in mice lacking the xeroderma pigmentosum group A gene. 767 85

Xeroderma pigmentosum patients with a defect in the nucleotide-excision repair gene XPA are characterized by, for example, a > 1,000-fold higher risk of developing sunlight-induced skin cancer. Nucleotide-excision repair (NER) is involved in the removal of a wide spectrum of DNA lesions. The XPA protein functions in a pre-incision step, the recognition of DNA damage. To permit the functional analysis of the XPA gene in vivo, we have generated XPA-deficient mice by gene targeting in embryonic stem cells. The XPA-/-mice appear normal, at least until the age of 13 months. XPA-/-mice are highly susceptible to ultraviolet (UV)-B-induced skin and eye tumours and to 7,12-dimethylbenz[a]anthracene (DMBA)-induced skin tumours. We conclude that the XPA-deficient mice strongly mimic the phenotype of humans with xeroderma pigmentosum.
Nature 1995 Sep 14
PMID:Increased susceptibility to ultraviolet-B and carcinogens of mice lacking the DNA excision repair gene XPA. 767 86

Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder with sun sensitivity, markedly increased skin cancer susceptibility, and defective DNA repair without consistently identified symptoms of immune deficiency. We examined natural killer (NK) cell activity and interferon production in peripheral blood lymphocytes (PBL) of eight XP patients who had multiple primary skin cancers. The XP patients had normal numbers of T cells and NK cells, as well as normal lymphokine-activated killer cell activity and normal tumor necrosis factor-alpha production. Unstimulated NK cell function was 40% of normal controls in five XP patients, but was normal in three other XP patients. However, PBL from all the XP patients tested showed no enhancement of NK activity by the interferon inducer, polyinosinic acid:polycytidilic acid (polyIC) but enhancement by interferon-alpha was normal, suggesting an impairment in interferon production. Parallel studies in non-XP skin cancer patients revealed that both unstimulated and polyIC-enhanced NK activity were normal. Further investigation using PBL from XP patients revealed that the production of interferon-gamma after stimulation with interferon inducers (polyIC, interleukin 2, or K562 tumor cells) was 13-43% of normals. These data indicate that XP lymphocytes have a defect in production of interferons and suggest that defective interferon production, as well as DNA repair defects, may play an important role in the susceptibility of XP patients to skin cancer.
J Clin Invest 1993 Sep
PMID:Impaired interferon production and natural killer cell activation in patients with the skin cancer-prone disorder, xeroderma pigmentosum. 769 Jul 72

We have previously reported a cisplatin-resistant HeLa cell line featuring a cross-resistance to genotoxic stresses including ultraviolet (UV) radiation and an enhancement of plasmid reactivation. In this study, excision repair of UV-DNA adducts in this resistant cell line was investigated. Using alkaline elution analysis, this resistant cell line showed a 2-fold enhancement in damage incision-associated DNA strand breaks. Using a gel mobility shift assay, the resistant cells exhibited a 3-fold increase in nuclear proteins which specifically recognize UV-damaged DNA. However, the rate of repair synthesis in the resistant cells appeared to be the same as in their parental counterparts. Thus, recognition and incision activities, the early stage of excision repair, are altered in the resistant cells. The results suggest that phenotypic cross-resistance of this cell line to UV is probably due to an improved excision repair of UV-DNA adducts which is defective in xeroderma pigmentosum group A cells. The results are consistent with the conclusion that the early stage, including recognition and incision, of excision repair is critical in determining cellular sensitivity or resistance to DNA damage.
Mutat Res 1993 Sep
PMID:Apparent alterations in the early stage of excision repair of UV-induced DNA damages in a HeLa mutant cell line that is resistant to genotoxic stresses. 769 Sep 2

Nevoid basal cell carcinoma syndrome (NBCCS, Gorlin syndrome) is an autosomal dominant disorder, characterized primarily by multiple basal cell carcinomas, epithelium-lined jaw cysts, and palmar and plantar pits, as well as various other features. Loss of heterozygosity studies and linkage analysis have mapped the NBCCS gene to chromosome 9q and suggested that it is a tumor suppressor. The apparent sensitivity of NBCCS patients to UV and X-irradiation raises the possibility of hypersensitivity to DNA-damaging reagents or defective DNA repair being etiological in the disorder. The recent mapping of the Fanconi anaemia group C (FACC) and xeroderma pigmentosum complementing group A (XPAC) genes to the same region on 9q has led us to begin the molecular dissection of the 9q22-q31 region. PCR analysis of the presence or absence of 10 microsatellite markers and exons 3 and 4 of the XPAC and FACC genes, respectively, allowed us to order 12 YACs into an overlapping contig and to order the markers as follows: D9S151/D9S12P1-D9S12P2-D9S197-D9S196-D9 S280-FACC-D9S287/XPAC-D9S180-D9S6-D9 S176 . Sizing of the YACs has provided an initial estimate of the size of the NBCCS candidate region between D9S12 and D9S180 to be less than 1.65 Mb.
Genomics 1994 Sep 01
PMID:A YAC contig spanning the nevoid basal cell carcinoma syndrome, Fanconi anaemia group C, and xeroderma pigmentosum group A loci on chromosome 9q. 782 76


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