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)

Inhibition of HeLa cell DNA synthesis by DNA-damaging agents as a test for mutagenic carcinogens has been investigated further. Several mutagens and/or carcinogenic agents not previously assayed for DNA synthesis inhibition were tested and found to be positive. The effect of two DNA-damaging agents administered simultaneously was investigated: With ultraviolet light (UV) and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) the effects were partly additive, whereas with MNNG and ICR-170 they were not. When UV was administered simultaneously with hydroxyurea (HU), a non-DNA-damaging inhibitor of DNA synthesis, the effects of the DNA-damaging agent were still evident after HU was removed and the HU-induced DNA synthesis inhibition reversed. Therefore, although the test probably cannot determine whethter there are one or more DNA-damaging agents in an unknown mixture, the presence of a powerful DNA synthesis inhibitor that is not a DNA-damaging agent will not mask the effects of a DNA-damaging agent in the same sample. Despite the fact that ICR-170 induces little DNA repair in xeroderma pigmentosum (XP) cells, which are deficient in excision repair, the inhibition of DNA synthesis induced by this agent was less in XP cells than in HeLa cells. The inhibition of DNA synthesis by MNNG was also less in XP than in HeLa cells. Therefore, contrary to expectations, the use of a repair-deficient cell did not increase the sensitivity of the test. Various in vitro mammalian cell tests are compared. Assays for unscheduled DNA synthesis are much less sensitive to intercalating agents, such as adriamycin, and to X-rays than are assays for inhibition of DNA synthesis but takes longer and requires more specialized skills than does measurement of DNA synthesis inhibition. Finally, the in vitro HeLa DNA synthesis inhibition test is compared with the in vivo DNA synthesis inhibition test with mouse testes.
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PMID:DNA synthesis inhibition in HeLa cells as a simple test for agents that damage human DNA. 72 25

Trichothiodistrophy (TTD), xeroderma pigmentosum (XP), and Cockayne's syndrome (CS) are three distinct human diseases with sensitivity to ultraviolet (UV) radiation affected by mutations in genes involved in nucleotide excision repair (NER). Among the many responses of human cells to UV irradiation, both nuclear accumulation of p53, a tumor suppressor protein, and alterations in cell-cycle checkpoints play crucial roles. The purpose of this study was to define the signals transmitted after UV-C-induced DNA damage, which activates p53 accumulation in TTD/XP-D fibroblasts, and compare this with XP-D cell lines that carry different mutations in the same gene, XPD. Our results showed that p53 was rapidly induced in the nuclei of TTD/XP-D and XP-D fibroblasts in a dose-dependent manner after UV-C irradiation, as seen in XP-A and CS-A fibroblasts, much lower doses being required for the protein accumulation than in normal human fibroblasts, XP variant cells, and XP-C cells. The kinetics of accumulation of p53 and two effector proteins involved in cell-cycle arrest, WAF1 and GADD45, were also directly related to the repair potential of the cells, as in normal human fibroblasts their levels declined after 24 h, the time required for repair of UV-induced lesions, whereas NER-deficient TTD/XP-D cells showed p53, WAF1, and GADD45 accumulation for over 72 h after irradiation. Our results indicate that p53 accumulation followed by transcriptional activation of genes implicated in growth arrest is triggered in TTD/XP-D cells by the persistence of cyclobutane pyrimidine dimers, which are known to block transcription, on the transcribed strands of active genes.
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PMID:Prolonged p53 protein accumulation in trichothiodystrophy fibroblasts dependent on unrepaired pyrimidine dimers on the transcribed strands of cellular genes. 943 78

Induction of the p21(WAF1) protein (hereafter called p21) following genotoxic stress is known to inhibit proliferating cell nuclear antigen (PCNA)-dependent DNA repair, downregulate apoptosis, and trigger a sustained growth-arrested phenotype called accelerated senescence. Studies with immortalized human and murine cell lines have revealed that exposure to ultraviolet light (UVC; 254 nm) results in the degradation of p21 to facilitate DNA repair and promote cell survival, or may lead to apoptotic cell death. The objective of the present study was to determine whether exposure of non-transformed human fibroblast strains to relatively low fluences of UVC (i.e., fluences typically used in the clonogenic survival assay) might induce sustained nuclear accumulation of p21, leading to accelerated senescence. We have evaluated the responses of normal human fibroblast (NHF) strains and nucleotide excision repair (NER)-deficient fibroblast strains representing xeroderma pigmentosum (XP) complementation groups A and G and Cockayne syndrome (CS) complementation groups A and B. We report that exposure of NHFs to < or =15 J/m(2) of UVC, and NER-deficient fibroblasts to < or =5 J/m(2) of UVC, results in sustained nuclear accumulation of p21 and growth arrest through accelerated senescence. With each fibroblast strain examined, exposure to UVC fluences that resulted in approximately 90% loss of clonogenic potential triggered significant (>60%) accelerated senescence, but only marginal (<5%) apoptosis. We conclude that nuclear accumulation of p21 accompanied by accelerated senescence may be an integral component of the response of human fibroblasts to UVC-induced DNA damage, irrespective of their DNA repair capabilities.
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PMID:Ultraviolet light exposure triggers nuclear accumulation of p21(WAF1) and accelerated senescence in human normal and nucleotide excision repair-deficient fibroblast strains. 1789 9