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 aim of our work was to investigate whether DNA topoisomerase II participates in the repair-specific incision of UV-irradiated genomic DNA. Therefore, the influence upon DNA incision of the topoisomerase II inhibitors (nalidixic and oxolinic acid, novobiocin and coumermycin A1) as well as the intercalating agent quinacrine has been measured in normal human fibroblasts using the alkaline elution technique. In addition, inhibition by novobiocin has been determined in fibroblast strains from 11 normal donors and from 16 xeroderma pigmentosum (XP) patients belonging to the complementation groups A, C, D, E, and XP variant. Nalidixic and oxolonic acid did not inhibit endonucleolytic cleavage, whereas novobiocin was a potent inhibitor of DNA incision. It was observed that in normal and in all XP strains 50% inhibition by novobiocin occurred on average in the dose range 315-590 microM. Since inhibition by novobiocin was not paralleled by that with the other topoisomerase II inhibitors nalidixic and oxolinic acid, it must be concluded that reduction of enzyme-catalysed breaks was not due to the participation of topoisomerase II in the incision step, but to the displacement of ATP at the binding site of the DNA-incising enzyme. This enzyme absolutely requires ATP as a cofactor for endonucleolytic cleavage. Quinacrine, however, inhibited DNA incision in normal fibroblasts at a mean Ki of 318 microM. Inhibition by this intercalating agent seems to be caused by structural perturbations in DNA, which render it a poor substrate for endonucleolytic cleavage.
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PMID:The effects of inhibitors of topoisomerase II and quinacrine on ultraviolet-light-induced DNA incision in normal and xeroderma pigmentosum fibroblasts. 184

Abnormal expression of the nuclear-associated enzyme DNA topoisomerase II (topoisomerase II) has been implicated in the in vitro phenotype of radiation hypersensitive ataxia-telangiectasia (A-T) cells and in modifying sensitivity of eukaryotic cells to topoisomerase II-inhibitor drugs [e.g., the DNA intercalator amsacrine (mAMSA)]. To study such relationships, various SV40- and Epstein-Barr Virus-transformed human cell lines derived from normal, A-T, or UV-sensitive xeroderma pigmentosum donors have been assayed for their sensitivity to mAMSA together with direct and indirect measurements of topoisomerase II expression. We report on the identification of an SV40-transformed A-T fibroblast cell line with abnormally high levels of topoisomerase II in nuclear protein extracts as determined by immunoblotting, measurement of kinetoplast DNA decatenation activity, and mAMSA-dependent DNA-protein cross-linking activity in a filter binding assay. Using a flow cytometric assay for the analysis of reactivity of nuclei with a polyclonal antitopoisomerase II antibody, overproduction was found to occur in all phases of the cell cycle. High levels of topoisomerase II were associated with hypersensitivity (5-10-fold) to mAMSA-induced cell cycle delay, cell kill, and DNA strand breakage (assayed under protein-denaturing conditions). Xeroderma pigmentosum (group A) cells demonstrated normal responses to mAMSA. The results provide evidence that cellular potential for the generation of topoisomerase II-dependent DNA damage is a major factor in governing the sensitivity to mAMSA. Furthermore, underexpression of topoisomerase II does not appear to be a primary factor in describing the in vitro A-T phenotype. The findings also relate to how changes in chromatin structure and function may either reflect or dictate the expression of topoisomerase II in human cells.
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PMID:Cellular consequences of overproduction of DNA topoisomerase II in an ataxia-telangiectasia cell line. 253 42

DNA topoisomerase II is involved in DNA topologic changes through the formation of a cleavable complex. This is stabilized by the antitumor drug VP16, which results in DNA breakage, aberrant recombination, and cell death. In this work, we compare the chromosomal damage induced by VP16 with that induced by bleomycin (BLM) in lymphoblasts from patients affected by the chromosome breakage syndromes ataxia telangiectasia (AT), xeroderma pigmentosum (XP), and Bloom syndrome (BS), and by the progeroid syndromes Werner (WS) and Cockayne (CS). Patients affected by AT, XP, BS, and WS have a greatly enhanced risk of developing cancer. The results show that AF and WS cells are hypersensitive to VP16, as revealed in the higher proportion of metaphases showing exchange figures and more than two breaks. All lines except AT and one CS line showed normal sensitivity to BLM. Our data on the sensitivity to VP16 of all these mutant cells underline the fact that VP16 damage is amplified only in cells that have abnormal illegitimate recombination (i.e., AT and WS).
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PMID:Effects of topoisomerase II inhibition in lymphoblasts from patients with progeroid and "chromosome instability" syndromes. 862 55

DNA topoisomerase II was monitored with the monoclonal antibody Ki-S1 in human fibroblasts after irradiation of cells with 254-nm UV light and -rays from a 137Cs source. DNA topoisomerase II was localized immunohistochemically as bright fluorescent dots in the karyoplasm. Investigated fibroblasts originated from normal human donors and a xeroderma pigmentosum patient (XP12BE). All cell lines showed a time and dose-dependent increase in DNA topoisomerase II abundance after irradiation. The increase may reflect enhanced accessibility of the enzyme, enhanced gene expression or enhanced stabilization of mRNA or protein molecules. The effect was detectable as early as 1 h after irradiation at doses 3 J/m2 or 3 Gy. It passed through a maximum and decreased within 18 h (UV light) or 6 h ( -rays). Except for the duration of the response, no principal differences were seen between the effects caused by UV light and those elicited by -rays. The increase in enzyme levels might be part of the well-known DNA damage responses which operate in cell-protective or DNA-reparative pathways or may reflect initiation of apoptosis. DNA topoisomerase I was detected with a commercially available polyclonal antibody raised against human DNA topoisomerase I. In unirradiated cells, DNA topoisomerase I was found to be mainly concentrated in nucleoli. Irradiation with -rays changed the staining pattern in that it caused a multitude of DNA topoisomerase I-rich centers to occur which may reflect sites of transcription of radiation-inducible genes.
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PMID:Irradiation with ultraviolet light and gamma-rays increases the level of DNA topoisomerase II in nuclei of normal and xeroderma pigmentosum fibroblasts. 945 48

DNA topoisomerase IIalpha was monitored with the monoclonal antibody Ki-S1 in human fibroblasts after irradiation of cells with gamma rays from a 137Cs source or treatment with the DNA topoisomerase II inhibitor doxorubicin. DNA topoisomerase IIalpha was localized immunohistochemically as bright fluorescent dots in the karyoplasm. The fibroblasts investigated originated from normal human donors and a xeroderma pigmentosum (XP) patient (XP12BE). All cell lines examined showed a time- and dose-dependent increase in DNA topoisomerase IIalpha abundance after irradiation or treatment with doxorubicin. No principal difference in response was seen between normal and XP fibroblasts towards either treatment alone. After irradiation with 9 Gy, the effect was detectable after as little as 30 min and lasted for at least 6 h. After doxorubicin treatment, topoisomerase II overexpression occurred within less than 2 h. It passed through a maximum and began to decrease after approximately 6 h. In principle, the increase in DNA topoisomerase IIalpha may result from (i) architectural changes of interphase chromatin leading to enhanced accessibility of preformed enzyme to the antibody, (ii) enhanced gene expression, or (iii) enhanced stabilization of mRNA or protein molecules. The increase in enzyme levels may be part of the well-known DNA damage responses that operate in cell-protective or DNA-reparative pathways. Thus, the action of DNA topoisomerase II would serve to catalyze preparatory steps in DNA repair. We also found overexpression of the Bax protein and p16 predominantly in treated XP cells, suggesting that the DNA-damaging protocols elicited signals for apoptosis and cell-cycle arrest. From the simultaneous increase in DNA topoisomerase IIalpha and Bax, one may conclude that DNA topoisomerase IIalpha also plays role in apoptosis.
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PMID:Doxorubicin and gamma rays increase the level of DNA topoisomerase IIalpha in nuclei of normal and xeroderma pigmentosum fibroblasts. 971 98

Etoposide is a widely used anticancer drug and a DNA topoisomerase II (Top2) inhibitor. Etoposide produces Top2-attached single-strand breaks (Top2-SSB complex) and double-strand breaks (Top2-DSB complex) that are thought to induce cell death in tumor cells. The Top2-SSB complex is more abundant than the Top2-DSB complex. Human tyrosyl-DNA phosphodiesterase 2 (TDP2) is required for efficient repair of Top2-DSB complexes. However, the identities of the proteins involved in the repair of Top2-SSB complexes are unknown, although yeast genetic data indicate that 5' to 3' structure-specific DNA endonuclease activity is required for alternative repair of Top2 DNA damage. In this study, we purified a flap endonuclease 1 (FEN1) and xeroderma pigmentosum group G protein (XPG) in the 5' to 3' structure-specific DNA endonuclease family and synthesized single-strand break DNA substrates containing a 5'-phoshotyrosyl bond, mimicking the Top2-SSB complex. We found that FEN1 and XPG did not remove the 5'-phoshotyrosyl bond-containing DSB substrates but removed the 5'-phoshotyrosyl bond-containing SSB substrates. Under DNA repair conditions, FEN1 efficiently repaired the 5'-phoshotyrosyl bond-containing SSB substrates in the presence of DNA ligase and DNA polymerase. Therefore, FEN1 may play an important role in the repair of Top2-SSB complexes in etoposide-treated cells.
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PMID:FEN1 participates in repair of the 5'-phosphotyrosyl terminus of DNA single-strand breaks. 2658 Dec 12