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)

Ten lines of skin fibroblasts from individuals with genetic disorders predisposing to a high risk of cancer were compared with nine lines from normal adult donors with respect to chromatid damage after x-irradiation [25, 50, and 100 rad (0.25, 0.50, and 1 gray)] during G2 phase. The 10 cell lines represented five genetic disorders: Bloom syndrome, familial polyposis, Fanconi anemia, Gardner syndrome, and xeroderma pigmentosum, complementation groups A(XP-A), C(XP-C), E(XP-E), and variant (XP-Va). The incidence of chromatid breaks in all cancer-prone lines except XP-E and XP-A was significantly higher than in the normal lines. The incidence of chromatid gaps in all cancer-prone lines except XP-A and XP-Va was significantly higher than in the normal lines. Because each chromatid apparently contains a single continuous DNA double strand, chromatid breaks and gaps represent unrepaired DNA strand breaks arising directly or indirectly during excision repair of x-ray-induced DNA damage. These cytogenetic data together with results from use of the DNA repair inhibitor arabinofuranosyl cytosine (cytosine arabinoside) suggest that cells from all of these cancer-prone individuals are deficient in some step of DNA repair, predominantly excision repair operative during the G2-prophase period of the cell cycle. It appears that these DNA repair deficiencies are associated with a genetic predisposition to a high risk of cancer.
Proc Natl Acad Sci U S A 1983 Sep
PMID:Chromatid damage after G2 phase x-irradiation of cells from cancer-prone individuals implicates deficiency in DNA repair. 657 47

Antipain had little effect on UV-survival and UV-induced sister chromatid exchanges in normal and xeroderma pigmentosum (XP) cells, suggesting that it may not affect DNA repair. Antipain itself produced a small, but significant, amount of sister chromatid exchanges. XP cells showed very high sensitivity to the cytotoxic effect of antipain, but an SV40-transformed XP cell strain did not demonstrate high sensitivity.
Cancer Lett 1980 Sep
PMID:Cytotoxic effects of protease inhibitors on human cells. 1. High sensitivity of xeroderma pigmentosum cells to antipain. 700 Mar 35

DNA repair in mouse cells derived from embryos of 3 inbred strains were investigated in comparison with that in human cells. The levels of unscheduled DNA synthesis after UV irradiation appeared to change at different passages, but capacities of host-cell reactivation of UV-irradiated herpes simplex virus were always reduced to the same levels as those in xeroderma pigmentosum cells. This implied that mouse cells are reduced in excision-repair capacities and that the apparently high levels of unscheduled DNA synthesis at certain passages are not quantitatively related to high levels of cell survival. Essentially no differences in DNA repair were noted among 3 strains--BALB/c, C3H/He and C57BL/10.
Mutat Res 1982 Sep
PMID:DNA repair ability of cultured cells derived from mouse embryos in comparison with human cells. 712 99

Heterozygous carriers of an ataxia-telangiectasia (A-T), Fanconi anemia (FA), or xeroderma pigmentosum (XP) gene may be predisposed to some of the same congenital malformations or developmental disabilities that are common among homozygotes. To test this hypothesis, medical records, death certificates, and questionnaires from 27 A-T families, 25 FA families, and 31 XP families were reviewed. Eleven XP blood relatives (out of 1,100) were found with moderate or severe unexplained mental retardation, a significant excess compared to the FA and A-T families (3/1,439). There were four microcephalic XP blood relatives and none in the FA or A-T families. In the A-T families, idiopathic scoliosis and vertebral anomalies were in excess, while genitourinary and distal limb malformations were found in the FA families. A-T, FA, or XP heterozygotes may constitute an important proportion of individuals at risk for specific malformations or developmental abnormalities.
Am J Hum Genet 1982 Sep
PMID:Congenital malformations and developmental disabilities in ataxia-telangiectasia, Fanconi anemia, and xeroderma pigmentosum families. 712 32

The sensitivity of a number of human fibroblast cell strains towards the DNA intercalating and mutagenic agent ethidium bromide has been examined. Among the cell strains investigated, 3 were of fetal origin, 6 from clinically normal adult persons, 2 from Lesch-Nyhan individuals and 1 each from persons with 3 genetic disorders, xeroderma pigmentosum, Fanconi anemia and Bloom syndrome, which are known to predispose to cancer. Results of our studies show that cells derived from 2 otherwise normal individuals exhibits a marked sensitivity towards ethidium bromide as compared to the rest of the group. At the same time all 3 cell strains of fetal origin were found to be highly resistant to killing by this agent. These results are discussed in relation to the toxic/mutagenic effects of ethidium bromide.
Mutat Res 1982 Sep
PMID:Human fibroblast strains showing increased sensitivity or resistance to ethidium bromide. 714 89

A non-sensitive, 8-yr-old male patient (termed UV81KO) with only acute recurrent sunburns and without any other physical or neuromental retardations was studied. The patient's skin exhibited lowered minimal erythema doses between 280 and 300 nm monochromatic wavelengths without delayed peaking of erythema. UV81KO skin fibroblasts in culture was 5-fold more sensitive to 254 nm UV killing than normal cells, though the response of obligatory heterozygotes was normal. UV81KO cells were also more sensitive to killings by fluorescent sunlamp (295-300 nm UV-B) radiation, 4-nitroquinoline-1-oxide, and N-hydroxy-acetyl aminofluorene, but not by monofunctional decarbamoyl mitomycin C, bifunctional mitomycin C, and alkylating agents (methyl methanesulfonate, ethyl methanesulfonate, N-methyl-N-nitrosourea). Assays for unscheduled DNA synthesis, T4 endonuclease V-susceptible sites (pyrimidine dimers), endogenous excision-break accumulation by arabinofuranosyl cytosine-plus-hydroxyurea, single-strand-break rejoining, and molecular-weight increase of pulse-chased DNA in irradiated cells indicated no apparently detectable defects in nucleotide-excision repair processes and in replicative bypass in UV81KO cells. Despite the repair proficiency as such, UV81KO cells showed the defective recovery of DNA synthesis after 254 nm UV irradiation with 1 and 5 J/m2, at which dose the recovery occurred in normal cells. The base line level of sister-chromatid exchanges (SCEs) was higher in UV81KO cells (10-12 SCEs/cell) than in normal cells (5 SCEs/cell), although the induction rate of SCEs by 254 nm UV in UV81KO cells was the same as in normal cells. Such clinical, cellular and molecular characteristics and comparison to those in the other photodermatoses (xeroderma pigmentosum, Cockayne's syndrome, the 11961 disorder, Bloom's syndrome) can make a clear distinction of UV81KO from the others. Thus, the UV81KO disorder is put forward as a new photodermatosis with a defect in the recovery of post-UV DNA synthesis.
J Invest Dermatol 1981 Sep
PMID:A new human photosensitive subject with a defect in the recovery of DNA synthesis after ultraviolet-light irradiation. 726 57

33 chemical agents and UV- and gamma-irradiation were tested for their comparative ability to induce long-patch or short-patch repair using the 5-bromodeoxy-uridine photolysis assay. For 11 chemical agents repair was long-patch in nature as determined by calculated patch size and response of xeroderma pigmentosum cells relative to normal human cells. Typical patch sizes as measured by this assay were about 90 nucleotides for UV repair, a range of 30 to 70 nucleotides for a variety of known and suspected UV-mimetic chemicals, and 3-4 nucleotides for gamma-radiation. Alkylating agents previously shown to induce short-patch repair were shown also to induce long-patch repair.
Mutat Res 1981 Sep
PMID:Classification of chemical agents as to their ability to induce long- or short-patch DNA repair in human cells. 730 Aug 47

Skin fibroblasts from ataxia telangiectasia and xeroderma pigmentosum (XP) donors and from the XP sib (possible heterozygote), all genetically predisposed to a high risk of cancer, show an increased susceptibility to light-induced chromatid breaks after culture in vitro. Light-induced chromatid breaks were shown previously to result from generation of hydrogen peroxide (H2O2) during light exposure. The level of susceptibility attained is significantly higher than that observed in 13 lines of fibroblasts from normal skin of donors ranging in age from 3 days to 92 years or from fetal skin tested at various population doubling levels. Two lines of normal skin fibroblasts transformed by chemical carcinogens to neoplastic cells also show a significant increase in susceptibility as compared with their untransformed controls. These data indicate for human cells, as reported earlier for mouse cells, an association between enhanced susceptibility to light-induced chromatid damage and neoplastic potential; this association is further supported by the high susceptibility of cells derived from a human adenocarcinoma. Two observations are consistent with the concept that the increased susceptibility does not result from greater initial damage to the DNA of the neoplastic cells. First, activities of the ubiquitous H2O2 scavenging enzyme, glutathione peroxidase, are similar in the paired normal and neoplastic cell populations. Second, cells of the paired lines are equally sensitive to DNA breakage by exogenous H2O2. The enhanced susceptibility associated with neoplastic potential may result from an impaired capacity to repair DNA rather than a greater initial sensitivity of the neoplastic cells to the damaging agent.
Int J Cancer 1981 Sep 15
PMID:Light-induced chromatid damage in human skin fibroblasts in culture in relation to their neoplastic potential. 731 76

Endonuclease V of bacteriophage T4 possesses two enzymatic activities, a DNA N-glycosylase specific for cyclobutane pyrimidine dimers (CBPD) and an associated apurinic/apyrimidinic (AP) lyase. Extensive structural and functional studies of endonuclease V have revealed that specific amino acids are associated with these two activities. Controversy still exists regarding the role of the aromatic amino acid stretch close to the carboxyl terminus, in particular the tryptophan at position 128. We have expressed wild-type and mutant W128S endonuclease V in Escherichia coli from an inducible tac promoter. Purified W128S endonuclease V demonstrated substantially decreased N-glycosylase (approximately 5-fold) and AP lyase (10- to 20-fold) activities in vitro compared to the wild-type enzyme when a UV-irradiated poly(dA)-poly(dT) substrate was used. However, a much smaller difference in AP lyase activity between the two forms was observed with a site-specific abasic oligonucleotide. The difference in enzymatic activity was qualitatively, but not quantitatively, reflected in the survival of UV-irradiated bacteria, that is the W128S cells were slightly less UV resistant than wild-type cells. No difference was observed in the complementation of UV repair using UV-damaged denV- T4 phage. A more pronounced difference between the wild-type and W128S proteins was observed in human xeroderma pigmentosum group A cells by host-cell reactivation of a UV-irradiated reporter gene. The relatively large discrepancy between the in vitro and in vivo results observed with bacteria may be because saturated levels of DNA repair are obtained in vivo with relatively low levels of endonuclease V. However, under limiting in vitro conditions and in human cells in vivo a considerable difference between the W128S mutant and wild-type endonuclease V activities can be detected. Our results demonstrate that tryptophan-128 is important for endonuclease V activity.
Nucleic Acids Res 1995 Sep 25
PMID:Replacing tryptophan-128 of T4 endonuclease V with a serine residue results in decreased enzymatic activity in vitro and in vivo. 747 8

Mutagenicity and carcinogenicity of the ubiquitous environmental pollutant benzo[a]pyrene is mediated via its reactive diol epoxide metabolite, anti-BPDE, with the predominant formation of N(2)-deoxyguanine adducts in genomic DNA. Polyclonal and monoclonal antibodies specific for (+/-)-anti-BPDE DNA adducts were used for the quantitative detection of genotoxic damage in DNA treated in vitro and in vivo with ( +/- )-anti-BPDE. In non-competitive enzyme-linked immunosorbent assay the polyclonal antiserum (BP1) exhibited higher affinity, avidity and sensitivity than the monoclonal antibody (5D2). A linear antibody binding response was observed over a wide carcinogen dose range with a detection limit of < 0.1 fmol adducts in immobilized DNA. Non-competitive immuno-slot blot assay could detect 0.2 adducts/10(6) nucleotides induced by < 1 nM ( +/- )-anti-BPDE. The high sensitivity and mono-adduct specificity of non-competitive immunoassays allowed the detailed study of ( +/- )-anti-BPDE-DNA adduct processing human cells exposed to very low levels of the genotoxin. Analysis of polyclonal antiserum binding sites in DNA from repair-proficient human fibroblasts revealed adduct removal rates directly proportional to the initial genotoxic insult. Despite efficient repair, substantial damage persisted in repair-proficient cells exposed to high doses of carcinogen. At low levels of initial damage (0.882 and 3.44 +/- 0.17 adducts/ 10(6) nucleotides) approximately 50% repair was observed after 4 and 8 h respectively. Cells removed approximately 40% of the lesions in 8 h at an intermediate level of damage (20.7 +/- 1.5 adducts/10(6) nucleotides). At higher DNA damage levels (105 +/- 8 and 177 +/- 1 adduct/10(6) nucleotides) 33 and 19% of the lesions respectively were repaired in 24 h. Repair-deficient xeroderma pigmentosum group A fibroblast cells did not show any significant loss of antibody binding sites at high or low initial modification levels. These data suggest that the level of initial DNA damage has a significant impact on the overall efficiency of cellular repair, with potential implications for the biological consequences of deleterious DNA lesions in mammalian cells.
Carcinogenesis 1995 Sep
PMID:DNA repair in human cells: quantitative assessment of bulky anti-BPDE-DNA adducts by non-competitive immunoassays. 755 50


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