Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Human hereditary diseases such as xeroderma pigmentosum, Fanconi's anemia, ataxia telangiectasia, and Bloom's syndrome are characterized by a proneness for developing cancer associated with abnormalities in the processing of DNA damage. The molecular defects responsible for predisposing human tissues to cancer are still not well understood, despite the fact that a considerable amount of work has already been done on this problem. In this paper, we show that in human tumor cell lines, in cells transformed by DNA tumor viruses, and in cells derived from certain cancer-prone disorders, the level of activity of a 42-kDa deoxyribonuclease is many times higher than in diploid untransformed control cells. This suggests that this activity is linked to, or may play a role in, malignant transformation.
Mol Carcinog 1989
PMID:Enhanced deoxyribonuclease activity in human transformed cells and in Bloom's syndrome cells. 280 19

We wished to determine whether simian virus 40 (SV40)-transformed xeroderma pigmentosum cells, despite their defective DNA repair, were suitable for DNA-mediated gene transfer experiments with linked genes. Expression of a nonselectable gene (cat, coding for chloramphenicol acetyltransferase [CAT]) linked to a selectable gene (gpt, coding for xanthine-guanine phosphoribosyltransferase [XPRT]) in the plasmid pSV2catSVgpt was quantified after transfection of SV40-transformed xeroderma pigmentosum [XP20s(SV40)] and normal human [GM0637(SV40)] fibroblast cell lines. A novel autoradiographic assay with [3H]xanthine incorporation showed 0.5 to 0.7% phenotypic expression of XPRT in both cell lines. Without selection, transient CAT activity was 20 times greater in the GM0637(SV40) than in the XP20s(SV40) cells, and transient XPRT activity was 5 times greater. Both of these transient activities were increased and equalized in both cell lines by transfection with pRSVcat or pRSVgpt. Genotypic transformation to gpt+ occurred at a frequency of 2 X 10(-4) to 4 X 10(-4) in both cell lines with pSV2catSVgpt. After 2 to 3 months in selective medium, stable expression of the (nonselected) cat gene was found in 11 (92%) of 12 gpt-containing clones derived from GM0637(SV40) cells and in 13 (81%) of 16 gpt-containing clones from XP20s(SV40) cells. However, the levels of CAT activity did not correlate with those of XPRT activity, and both of these activities varied more than 100-fold among different clones. Copies (1 to 4) of the gpt gene were integrated in four clones of the GM0637(SV40) cells having an XPRT activity of 1 to 5 nmol/min per mg, but 5 to 80 copies were integrated in four XP20s(SV40) clones with an XPRT activity of 0.8 to 1.8 nmol/min per mg. This study shows that XP20s(SV40) is as suitable for gene transfer experiments as the normal human line GM0637(SV40).
Mol Cell Biol 1985 Jul
PMID:Quantification of expression of linked cloned genes in a simian virus 40-transformed xeroderma pigmentosum cell line. 299 46

We have examined several parameters which address the feasibility of complementing the UV-sensitive phenotype of xeroderma pigmentosum (XP) fibroblasts by gene transfer. We present a comparative study which demonstrates that, relative to immortalized cells, human diploid cells are poor recipients for gene transfer. As measured by both transient and stable expression assays, diploid fibroblasts were completely refractory to DNA transfer by calcium phosphate coprecipitation and exhibited substantially reduced levels of expression following gene transfer by fusion with E. coli protoplasts. We also examined the significance of reversion of the phenotype of UV sensitivity in SV40-immortalized XP-A cell lines. In addition to confirming a previous report of reversion to wild-type levels of UV resistance at a frequency of approximately 10(-7), we have attempted to facilitate the identification of XP-A cells complemented with genomic DNA by employing less stringent selection schemes and cotransfection of a selectable marker. Under these conditions, we observed an increased frequency of reversion and were unable to identify true transfectants.
Somat Cell Mol Genet 1985 Nov
PMID:Studies on gene transfer and reversion to UV resistance in xeroderma pigmentosum cells. 300 3

A simian virus 40 (SV40) DNA fragment, encompassing the whole early region and having a defective origin of DNA replication, has been used to transform human fibroblast cells derived from two xeroderma pigmentosum (XP) patients. Two of the SV40-transformed XP cell lines, belonging to complementation group C, had acquired the characteristic of indefinite life-span in culture. These XP cell lines synthesize T antigen as shown by immunofluorescence and retain the high sensitivity to UV irradiation. Detailed karyotype analysis shows very few chromosomal changes, while the transfecting SV40 DNA is integrated into cellular DNA sequences. These are the first immortalized XP cell lines derived from complementation group C. In view of the extreme difficulty in obtaining immortalized human fibroblasts, we suggest a possible advantage of replication defective SV40 DNA molecules for immortalizing human fibroblast cells of any source.
Somat Cell Mol Genet 1986 Jan
PMID:Immortalization of xeroderma pigmentosum cells by simian virus 40 DNA having a defective origin of DNA replication. 300 28

We have compared the sites of nucleotide incision on DNA damaged by oxidizing agents when cleavage is mediated by either Escherichia coli endonuclease III or an endonuclease present in bovine and human cells. E. coli endonuclease III, the bovine endonuclease isolated from calf thymus, and the human endonuclease partially purified from HeLa and CEM-C1 lymphoblastoid cells incised DNA damaged with osmium tetroxide, ionizing radiation, or high doses of UV light at sites of pyrimidines. For each damaging agent studied, regardless of whether the E. coli, bovine, or human endonuclease was used, the same sequence specificity of cleavage was observed. We detected this endonuclease activity in a variety of human fibroblasts derived from normal individuals as well as individuals with the DNA repair deficiency diseases ataxia telangiectasia and xeroderma pigmentosum. The highly conserved nature of such a DNA damage-specific endonuclease suggests that a common pathway exists in bacteria, humans, and other mammals for the reversal of certain types of oxidative DNA damage.
Mol Cell Biol 1987 Jan
PMID:A highly conserved endonuclease activity present in Escherichia coli, bovine, and human cells recognizes oxidative DNA damage at sites of pyrimidines. 303 65

A group A xeroderma pigmentosum revertant with normal sensitivity was created by chemical mutagenesis. It repaired (6-4) photoproducts normally but not pyrimidine dimers and had near normal levels of repair replication, sister chromatid exchange, and mutagenesis from UV light. The rate of UV-induced mutation in a shuttle vector, however, was as high as the rate in the parental xeroderma pigmentosum cell line.
Mol Cell Biol 1987 Sep
PMID:Unique DNA repair properties of a xeroderma pigmentosum revertant. 311 97

To determine whether DNA excision repair is enhanced in mammalian cells in response to DNA damage, as it is in bacteria as part of the SOS response, we used an expression vector-host cell reactivation assay to measure cellular DNA repair capacity. When UV-damaged chloramphenicol acetyltransferase (CAT) vector DNA was introduced into monkey cells (CV-1), the level of CAT activity was inversely related to the UV fluence due to inhibition of CAT gene expression by UV photoproducts. When CV-1 cells were treated with either UV radiation or mitomycin C, 24-48 h before transfection, CAT expression from the UV-irradiated plasmid was increased. This increase also occurred in a line of normal human cells, but not in repair-deficient human xeroderma pigmentosum cells. We confirmed that this increase in CAT expression was due to repair, and not to production of damage-free templates by recombination; the frequency of generation of supF+ recombinants after transfection with UV-irradiated pZ189 vectors carrying different point mutations in the supF gene did not significantly increase in carcinogen-treated CV-1 cells. From these results we conclude that carcinogen treatment enhances the excision-repair capacity of normal mammalian cells.
Somat Cell Mol Genet 1988 Jul
PMID:Enhancement of DNA repair capacity of mammalian cells by carcinogen treatment. 313 2

The ultraviolet light-sensitive phenotype of xeroderma pigmentosum (XP) has been corrected by the incorporation into XP cells of small chromosome fragments from Chinese hamster ovary cells. Like normal human and hamster cells, these XP-hamster hybrids are able to excise both of the photoproducts produced by ultraviolet light: cyclobutane pyrimidine dimers and the minor photoproduct, (6-4) pyrimidine-pyrimidone dimers. This excision capacity contrasts with that of an XP revertant, of the same cell line used in this study, which is able to excise only the (6-4) photoproducts. The excision defect of XP has been fully corrected in the hybrids; therefore, the small hamster chromosome fragments they contain should carry the gene for complementation group A of XP.
Somat Cell Mol Genet 1987 Nov
PMID:Correction of excision repair in xeroderma pigmentosum by hamster chromosome fragments involves both classes of pyrimidine dimers. 347 16

Xeroderma pigmentosum (XP) is an inherited disease characterized by the defective repair of DNA damaged by ultraviolet radiation and a number of chemicals. In this paper, plasmid DNA carrying a marker gene is cross-linked in vitro by the antitumor drug cisplatin and successfully introduced into tissue culture cells by both calcium phosphate coprecipitation and electroporation. Transient expression of the marker gene is greatly decreased in XP cells compared to wild-type. As few as seven lesions will inactivate the marker gene in XP cells. Furthermore, the biochemical defect must include an impaired capacity for repair of cisplatin-DNA intrastrand cross-links. Since the host cell itself is not exposed to chemical modification, a cisplatin cross-linked plasmid shuttle vector can be used as a specific probe for the DNA repair capacity of cultured cells. Paradoxically, when cisplatin cross-linked plasmid carrying the selectable marker neo is introduced into cells, there is an increase in the number of stable neo+ transformants in both XP and wild-type cells. Thus, cisplatin damage appears to stimulate the integration of transfected DNA into the host chromosome by a mechanism that is independent of the defective repair pathway in XP.
Mol Biol Med 1987 Oct
PMID:DNA cross-linked by cisplatin: a new probe for the DNA repair defect in xeroderma pigmentosum. 369 39

It has been shown previously that the synthesis of small nuclear RNAs (snRNAs) U1, U2, U3, U4, and U5, in contrast to that of all other RNA species tested, decreases markedly within 2 h of cell incubation after exposure to UV light (254 nm), while pyrimidine dimers are being removed from DNA. We examined the possibility that the postirradiation cell incubation-dependent, UV light-induced inhibition of snRNA synthesis might reflect hypersensitivity of the snRNA transcriptional domains to single-stranded DNA nicks or relaxation of DNA torsional stress or both that occur during DNA repair. This late suppression of snRNA biosynthesis was as pronounced in UV light-irradiated (DNA incision-deficient) xeroderma pigmentosum fibroblasts (complementation group A) as in irradiated normal human fibroblasts. The synthesis of snRNAs was not preferentially sensitive to gamma radiation (which produces single-stranded DNA breaks) or novobiocin or nalidixic acid (which induce DNA relaxation). Neither of these two drugs prevented the UV light-induced inhibition of snRNA synthesis observed during postirradiation cell incubation. These results suggest that the late suppression of snRNA synthesis does not result from hypersensitivity of snRNA transcriptional domains to single-stranded DNA cleavages or relaxation of DNA torsional strain. The UV light-induced late inhibition of snRNA synthesis: shows an inactivation curve whose slope differs from that observed immediately after irradiation; is seen in untransformed cells as well as established cells lines; and has been conserved between birds and mammals.
Mol Cell Biol 1986 Mar
PMID:Effect of UV light on small nuclear RNA synthesis: increased inhibition during postirradiation cell incubation. 377 92


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