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)

The activities of DNA polymerases alpha, beta, and gamma were determined in control and repair-deficient human fibroblasts (xeroderma pigmentosum complementation groups A, C, and D; Fanconi's Anemia; and Bloom's syndrome). Assays were done on 103,000XG supernatants which had been chromatographed on DEAE cellulose to remove nucleic acids and on fractions containing polymerase activities which had been separated from one another on a second DEAE cellulose column. All repair-deficient cell types contained all three DNA polymerase activities. Caffeine, which has been observed to inhibit some DNA-repair processes in intact cells, had no effect on DNA polymerase activities from XP-A, XP-C, XP-D or XP-variant cells. These data indicate that all three polymerases are present in cells which have reduced or absent repair functions and that the caffeine effects observed in living cells are probably not due to the direct action of caffeine on DNA polymerases.
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PMID:Levels of DNA polymerases alpha, beta, and gamma in control and repair-deficient human diploid fibroblasts 1. 89 83

In Japan, more than 400 patients with xeroderma pigmentosum (XP) have been registered. The major groups are XP-A and variant, while clinically mild types of XP with intermediate levels of unscheduled DNA synthesis (UDS) have recently been increasing. The classical type of XP-A and some of the XP-D patients exhibit neurologic abnormalities. XP individuals display a marked increase in the frequency of skin malignancy. Development of skin malignancies appears to be related to the level of DNA repair capacity; the lower the capacity, the earlier and more frequently the skin tumors develop. Furthermore, the incidence of internal malignancy in XP patients is at least ten times higher than that for the Japanese general population over the age of 40 years. Cultured fibroblasts from XP patients exhibit higher sensitivity not only to UVC but also to UVB. The cellular sensitivity to UVB may correlate to photosensitivity in vivo from a study on a group E patient who showed age-related changes in photosensitivity and cellular sensitivity to UVB. We have also reviewed current status of molecular genetics in XP.
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PMID:Xeroderma pigmentosum: recent clinical and photobiological aspects. 129 56

Xeroderma pigmentosum (XP) patients are extremely sensitive to ultraviolet (UV) light and suffer from a high incidence of skin cancers, due to a defect in nucleotide excision repair. The disease is genetically heterogeneous, and seven complementation groups, A-G, have been identified. Homologs of human excision repair genes ERCC1, XPDC/ERCC2, and XPAC have been identified in the yeast Saccharomyces cerevisiae. Since no homolog of human XPBC/ERCC3 existed among the known yeast genes, we cloned the yeast homolog by using XPBC cDNA as a hybridization probe. The yeast homolog, RAD25 (SSL2), encodes a protein of 843 amino acids (M(r) 95,356). The RAD25 (SSL2)- and XPBC-encoded proteins share 55% identical and 72% conserved amino acid residues, and the two proteins resemble one another in containing the conserved DNA helicase sequence motifs. A nonsense mutation at codon 799 that deletes the 45 C-terminal amino acid residues in RAD25 (SSL2) confers UV sensitivity. This mutation shows epistasis with genes in the excision repair group, whereas a synergistic increase in UV sensitivity occurs when it is combined with mutations in genes in other DNA repair pathways, indicating that RAD25 (SSL2) functions in excision repair but not in other repair pathways. We also show that RAD25 (SSL2) is an essential gene. A mutation of the Lys392 residue to arginine in the conserved Walker type A nucleotide-binding motif is lethal, suggesting an essential role of the putative RAD25 (SSL2) ATPase/DNA helicase activity in viability.
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PMID:RAD25 (SSL2), the yeast homolog of the human xeroderma pigmentosum group B DNA repair gene, is essential for viability. 133 9

To assess the contribution to mutagenesis of human DNA repair defects, the UV-irradiated shuttle vector plasmid pZ189 was propagated in fibroblasts derived from a xeroderma pigmentosum (XP) patient in DNA repair complementation group C. In comparison to results with DNA repair-proficient human cells (WI-38 VA13), UV-irradiated pZ189 propagated in the XP-C (XP4PA(SV)) cells showed fewer surviving plasmids and a higher frequency of mutated plasmids. Base sequence analysis of 67 mutated plasmids recovered from the XP-C cells revealed similar classes of point mutations and mutation spectrum, and a higher frequency of G:C to A:T transitions along with a lower frequency of transversions among plasmids with single or tandem mutations compared to plasmids recovered from the normal line. Most single-base substitution mutations (83%) occurred at G:C base pairs in which the 5'-adjacent base of the cytosine was thymine or cytosine. These results indicate that the DNA repair defects in XP-C, in comparison to data previously reported for XP-A, XP-D and XP-F, result in different UV survival and mutation frequency but in similar types of base substitution mutations.
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PMID:UV-induced base substitution mutations in a shuttle vector plasmid propagated in group C xeroderma pigmentosum cells. 137 4

The xeroderma pigmentosum complementation group D is defined by more than 30 unrelated individuals of whom less than half show major abnormalities of the central nervous system, once considered to be the hallmark of the group. Fibroblasts from the great majority of these individuals show very considerable sensitivity to UV light in vitro despite the fact that the cells carry out what appears to be substantial excision repair, as judged from repair synthesis and incision activity. This article reviews the XPD group and the defects in cellular DNA repair and examines the lack of correlation between repair and the appearance of neurological abnormalities. The article also discusses the recent awareness that at least some members of two other inherited conditions, trichothiodystrophy and Cockayne's Syndrome, carry mutations in the XPD gene.
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PMID:The XPD complementation group. Insights into xeroderma pigmentosum, Cockayne's syndrome and trichothiodystrophy. 137 8

Xeroderma pigmentosum (XP) is a rare autosomal recessive disease characterized by photosensitivity, a high incidence of cancer in sun-exposed portions of the skin and a reduced capacity to repair the u.v.-induced DNA damage. One of the XP mutations (XP-D) has also been identified in patients affected by trichothiodystrophy (TTD), a rare autosomal recessive disease characterized by brittle hair, mental and physical retardation, peculiar face and ichthyosis. However, in these patients there is no evidence of increased skin tumour incidence. Since an impairment of cell-mediated immunity has been proposed as a co-factor in the cancer proneness of XP patients, we investigated the involvement of immune defect(s) in five XP patients, five TTD patients, their parents, and 24 TTD relatives. We evaluated the phenotype of circulating lymphocytes, natural killer (NK) cell lytic activity, target cell binding of NK cells at single cell level and the effect of interferons (IFN) alpha and beta on NK cell activity. The relative proportion of CD3+ and CD4+ circulating lymphocytes was reduced in XP but not in TTD patients. NK cell lytic activity was decreased in XP patients and their mothers, but their fathers showed normal lytic activity. NK activity varied among TTD families: four out of five patients and their relatives presented low NK cell activity, and one family was normal. In TTD family members, NK activity increased after incubation with IFN-alpha or IFN-beta, but never reached normal values. In contrast, in XP patients and their mothers, the defect was almost completely corrected after in vitro incubation with IFN-alpha or IFN-beta. Our study indicates impaired NK lytic activity in the majority of TTD and XP patients and that this defect is present also in members of their families. In addition, XP patients present a low number of circulating T cells. These multiple abnormalities, together with DNA repair defects, could be related to the increased cancer risk in XP patients.
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PMID:Immune defects in families and patients with xeroderma pigmentosum and trichothiodystrophy. 153 35

An immortalized xeroderma pigmentosum cell line belonging to the complementation group D (XP-D) was transfected with a normal human cDNA clone library constructed in a mammalian expression vector. Following UV-irradiation-selection, a transformant having a stable, partially UV-resistant phenotype was isolated. A transfected cDNA of partial length was rescued from the transformant's cellular DNA by in vitro amplification, using expression-vector specific oligonucleotides as primers in a polymerase chain reaction (PCR). Expression of this cDNA complemented the UV sensitivity of the XP-D cell line to the UV-resistance levels characteristic of the primary transformant. The nucleotide sequence of the cDNA was determined. The deduced protein identified the cDNA as encoding for the beta subunit of casein kinase II (CKII-beta). Similar to the effect exerted by the truncated CKII-beta cDNA, expression of a cDNA clone encompassing the complete translated region of CKII-beta leads to XP-D cells partially resistant to UV-irradiation. However, transfection of CKII-beta cDNA could also partially complement the UV-sensitivity of a xeroderma pigmentosum cell line belonging to group C (XP-C). Analysis by Southern, Northern and RNAase mismatch cleavage techniques did not reveal any functional defect in the CKII-beta gene of cell lines derived from either 7 XP-D or 10 XP-C families. We therefore consider it unlikely that either the XP-D or the XP-C DNA repair deficiency is associated with a defect in the beta subunit of casein kinase II. Nevertheless, our findings suggest the possibility that the cell's response to DNA damage is modulated by CKII-dependent protein phosphorylation.
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PMID:Expression of the cDNA for the beta subunit of human casein kinase II confers partial UV resistance on xeroderma pigmentosum cells. 169 65

Human Xeroderma pigmentosum "normal" fibroblasts AS16 (XP4 VI) were transformed after transfection with a recombinant v-myb clone. In this clone (pKXA 3457) derived from avian myeloblastosis virus (AMV), the expression of the oncogene sequences is driven by the AMV U-5 LTR promoter. The transformed cells (ASKXA), which have integrated a rearranged v-myb oncogene, grow in agar, are not tumorigenic in nude mice, and express a 45-kDa v-myb protein. The HMW DNA of these cells transform chicken embryo fibroblasts. The c-Ha-ras oncogene is overexpressed in the ASKXA cells but not in the parental "normal" AS16 cells and a revertant clone (ASKXA Cl 1.1 G). Our results lead to the conclusion that the XP fibroblasts are phenotypically transformed by the presence of the transfected v-myb oncogene, which is able to induce an overexpression of the c-Ha-ras gene.
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PMID:v-myb transformation of Xeroderma pigmentosum human fibroblasts: overexpression of the c-Ha-ras oncogene in the transformed cells. 189 42

A 43-year-old man with xeroderma pigmentosum, XP97TO, was allocated to complementation group D. He had had moderate photosensitivity at age 1 year and freckles by age 6 but no neurologic abnormalities. Nevertheless, his fibroblasts in culture had the XP-D phenotype. They showed a sevenfold hypersensitivity to killing by 254 nm ultraviolet radiation and a diminished level (29%) of unscheduled DNA synthesis. Phototesting revealed delayed maximum erythema at 72 hours after UVB exposure and a lowered minimal erythema dose. Lentigo maligna developed on the patient's face, and a rapidly growing malignant schwannoma was found on the left trigeminal nerve. This may be the first case of a peripheral nervous tissue neoplasm in xeroderma pigmentosum.
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PMID:Malignant schwannoma associated with xeroderma pigmentosum in a patient belonging to complementation group D. 189 71

Chromosome analysis was carried out in cultured fibroblasts from unaffected skin of five unrelated xeroderma pigmentosum (XP) patients and nine family members. Structural chromosome changes were observed in cultures from all examined individuals. Furthermore, in one XPD patient and in one XPC patient and his parents, cytogenetically abnormal clones were detected. Some of these clones were present starting from the primary explant. This cytogenetic pattern is similar to that observed in an XPC patient previously studied by us. The analysis of breakpoint distribution from clonal and non-clonal chromosome rearrangements showed that some breakpoints were more frequent and common to different families or to different family members although definite evidence of preferential involvement of chromosome bands was not obtained. This investigation indicates that there is a consistent tendency toward chromosome instability in XP mutation carriers. The instability could be related to the multiple chromosome anomalies characterizing skin tumors in XP subjects.
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PMID:Chromosome rearrangements in normal fibroblasts from xeroderma pigmentosum homozygotes and heterozygotes. 198 53


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