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)

Immortalized fibroblasts from a male patient with xeroderma pigmentosum from complementation group D (XP-D) were treated with either ethyl methane sulfonate (EMS) or bleomycin (BLM) to obtain mutations in hypoxanthine phosphoribosyltransferase (HPRT) activity. The aneuploid parental cell line, MH3-XPD, was found to have a single copy of the HPRT gene, indicating that this cell line remained physically hemizygous for this locus during the transformation process. Subcloning of 6-thioguanine-resistant (6TG') isolates resulted in clones without detectable HPRT activity. Continued maintenance in elevated concentrations of 6TG (30-60 muM) produced cell populations with negligible growth in counterselection medium. No HPRT-deficient clones arose from unmutagenized cell cultures. Molecular analysis of the HPRT mutations in five clones with undetectable HPRT activity showed that four had large deletions. Two bleomycin-generated isolates were both found to have an approximately 28-kb intragenic deletion beginning with the first intron near exon 1 and ending within the fourth intron near exon 4. Messenger RNA from these clones was truncated by approximately 370 nucleotides. Our findings indicate that these two clones originated from the same mutational event within a founder cell. The three EMS-induced mutants fell into two classes: a putative point mutation or small deletion and two complete gene deletions.
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PMID:Ethyl methane sulfonate- and bleomycin-generated deletion mutations at HPRT locus in xeroderma pigmentosum complementation group D fibroblasts. 247 61

Cultured blood lymphocytes from 15 patients with Huntington's chorea (HC) and matched controls were exposed to a series of graded doses of mitomycin C and ethyl methane sulphonate and examined for the incidence of sister chromatid exchange (SCE). The spontaneous SCE levels did not differ between HC patients and controls and although cells from the majority of HC patients showed a slightly enhanced response to SCE induction by the mutagens, the enhancement was small and significant only on the pooled data. Cultures from 4 HC patients and controls were exposed to a graded series of X-ray exposures and no difference was observed in the spontaneous aberration frequencies between HC cells and controls, or in their response to aberration induction by X-rays. Skin fibroblast cultures derived from three HC patients, two xeroderma pigmentosum patients and two healthy controls were exposed to MMC and the levels of unscheduled DNA synthesis determined. There was no difference between the response of HC cells and normal controls, although such synthesis in the xeroderma cells was severely depressed. It is concluded that: (i) fibroblasts and lymphocytes from HC patients show a normal response to the three mutagens studied; (ii) there is no evidence for any defect in processes involved in repairing the lesions induced; (iii) the slightly elevated response of HC lymphocytes to SCE induction may reflect the presence of a different proportion of a slightly more sensitive T cell sub-set in HC patients, and (iv) HC cells do not show a hypersensitivity to mutagens that could be used as a basis for diagnosis.
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PMID:The response of cells from patients with Huntington's chorea to mutagen-induced chromosome damage. 621 3

In order to develop the usefulness of Fanconi's anemia (FA) lymphoblast lines for biochemical and genetic studies, we have determined their sensitivity to a variety of DNA-damaging chemicals. We have adapted a growth inhibiton protocol in which the sensitivity of a cell line is characterized by the drug concentration yielding a 50% inhibiton of growth (EC50). The DNA-cross-linking agents, mitomycin C, nitrogen mustard, melphalan, 1,3-butadiene diepoxide, cis-diaminedichloroplatinum(II), and cyclophosphamide, were all more toxic to four FA cell lines than to five normal lines. Three lines, HSC 72 (FA), 99 (FA) and 230 (FA), had EC50s that were 10 to 20 times lower than that of controls while the fourth line, HSC 62 (FA), had an intermediate EC50. Three nitrosourea compounds were also more toxic to FA cells than to controls. However, 2 normal cell lines (HSC 92 and 93) had nitrosourea EC50s 4 to 7 times lower than the other nine controls and overlapped the sensitivity of the intermediate [HSC 62 (FA)] cell line. The same 2 normal cell lines were also more sensitive than 12 other controls, including FA heterozygotes, xeroderma pigmentosum, and ataxia telangiectasis, to the monofunctional alkylating agents, ethyl methane sulfonate, methyl methane sulfonate, and N-methyl-N'-nitro-N-nitrosoguanidine. Heterogeneity was also found with FA lines. Two FA cell lines (HSC 72 and 230) had EC50s lower than all control lines while one FA line (HSC 99) had an EC50 similar to that of the resistant normal lines. FA and normal cells had nearly the same sensitivity to 4-nitroquinoline-1-oxide and bleomycin. These results demonstrate that FA lymphoblast lines are more sensitive than normal cell lines to all DNA-cross-linking agents examined. These cell lines should therefore be useful for the analysis of DNA cross-link repair and the biochemical defect in FA. We have also found an unexpected sensitivity of some FA and normal lines to monofunctional alkylating agents.
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PMID:Susceptibility of Fanconi's anemia lymphoblasts to DNA-cross-linking and alkylating agents. 680 8

In an enzymological approach to study DNA repair mechanisms induced by carcinogen-treatment of mammalian cells, we have investigated how DNA ligase activity is affected by the treatment with several compounds producing different DNA lesions. Stationary cultures of human fibroblasts were exposed to various doses of carcinogens (UV-light at 254 nm, N-acetoxy-acetyl-aminofluorene, ethyl-methane sulfonate, N-methylnitro-nitrosoguanidine, mitomycin C and 4-nitroquinoline-N-oxide) at different time-intervals before preparing crude cellular extracts and assaying for ligase activity. Results have shown that: 1. UV-irradiation, AAAF, 4NQO or MMC treatment of cells induces a two-fold increase in the ligase activity compared to control cells within 48 hours following the treatment. 2. A partial purification of the enzyme from these cellular crude extracts by sedimentation through sucrose gradients has shown: a. DNA ligase activity from control cells presents a profile composed of two distinct peaks sedimenting respectively at about 4S and 7S; b. the carcinogen treatment of either repair-proficient human fibroblasts or repair-deficient xeroderma pigmentosum cells (complementation group A) seems to induce a specific increase of the 4S-form of DNA ligase.
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PMID:DNA ligase activity in carcinogen-treated human fibroblasts. 681 22

Replication stress results in various forms of aberrant replication intermediates that need to be resolved for faithful chromosome segregation. Structure-specific endonucleases (SSEs) recognize DNA secondary structures rather than primary sequences and play key roles during DNA repair and replication stress. Holliday junction resolvase MUS81 (methyl methane sulfonate (MMS), and UV-sensitive protein 81) and XPF (xeroderma pigmentosum group F-complementing protein) are a subset of SSEs that resolve aberrant replication structures. To ensure genome stability and prevent unnecessary DNA breakage, these SSEs are tightly regulated by the cell cycle and replication checkpoints. We discuss the regulatory network that control activities of MUS81 and XPF and briefly mention other SSEs involved in the resolution of replication intermediates.
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PMID:Regulation of Structure-Specific Endonucleases in Replication Stress. 3055 28