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Query: UMLS:C0043346 (xeroderma pigmentosum)
 2,924 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Light emitted by electronic photographic flash units is shown to damage bacteria and human skin fibroblasts deficient in repair systems, with survival curves very similar to those produced by 254 nm short UV. The lesions induced by these flashes are as photorepairable by the photolyase enzyme as those induced by 254 nm UV and result in equivalent survival rates. Biological dosimetry performed with microorganisms highly sensitive to UV (Escherichia coli K12 AB2480, deficient in excision and recombinational-dependent repair systems and Bacillus subtilis UVSSP spores, deficient in excision and in a specific spore repair process) revealed that each 1 ms flash of light from the photographic unit used in this work contained the equivalent of 0.25 J m-2 of 254 nm UV, when measured at a distance of 7.0 cm. This dose of UV was found to be lethal to both repair-deficient E. coli bacteria and repair-deficient human skin fibroblasts obtained from xeroderma pigmentosum donors, as well as mutagenic in B/r wild-type and HCR-mutant bacteria.
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PMID:Damage to UV-sensitive cells by short UV in photographic flashes. 880 30

The mutational specificity of UV-light is characterized by an abundance of C to T transition mutations at dipyrimidines containing cytosine or 5-methylcytosine. A significant percentage of these mutations are CC to TT double transitions. Of the major types of UV-induced DNA lesions, the cis-syn cyclobutane pyrimidine dimers (CPDs) are thought to be the most mutagenic lesions, at least in mammalian cells. It has been proposed that the CPDs become mutagenic perhaps only after cytosine bases within these dimers deaminate to uracil and the resulting U-containing photolesions are correctly bypassed by DNA polymerases. In order to assess the significance of this proposed mutagenic mechanism, we have developed two methods to specifically measure deaminated CPDs in UV-irradiated human cells or DNA. The first method is based on enzymatic photoreversal of CPDs, followed by cleavage of the DNA with uracil DNA glycosylase, an AP lyase activity, and ligation-mediated PCR to map the resulting strand breaks. The second method, which can be used to detect double deamination events (CC to UU), is PCR amplification of photolyase-treated DNA using primers complemetary to the deaminated sequences. We have measured deamination events in the human p53 gene, which contains a large percentage of C to T transitions in skin cancers. The deamination reactions are specific for cytosine within CPDs, are negligible immediately after irradiation, and are time-dependent and DNA sequence context-dependent. Twenty four hours after irradiation of human fibroblasts with UVB light, between 10 and 60% of most CPD signals are converted to the deaminated form, depending on the sequence. Significant deamination occurs at skin cancer mutation sites in the p53 gene. Double deamination also occurs and this reaction can involve dimers containing 5-methylcytosine or cytosine. These double events are expected to occur more frequently in cells with a DNA repair defect because there is more time for deamination in unrepaired lesions. This may explain the relatively high frequency of CC to TT mutations in skin cancers from xeroderma pigmentosum patients. In summary, these novel detection techniques demonstrate that deamination of cytosine in pyrimidine dimers is a significant event that most likely contributes to the mutational specificity of UVB irradiation in human cells.
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PMID:Sequence and time-dependent deamination of cytosine bases in UVB-induced cyclobutane pyrimidine dimers in vivo. 981 19

Photoreactivation is one of the DNA repair mechanisms to remove UV lesions from cellular DNA with a function of the DNA photolyase and visible light. Two types of photolyase specific for cyclobutane pyrimidine dimers (CPD) and for pyrimidine (6-4) pyrimidones (6-4PD) are found in nature, but neither is present in cells from placental mammals. To investigate the effect of the CPD-specific photolyase on killing and mutations induced by UV, we expressed a marsupial DNA photolyase in DNA repair-deficient group A xeroderma pigmentosum (XP-A) cells. Expression of the photolyase and visible light irradiation removed CPD from cellular DNA and elevated survival of the UV-irradiated XP-A cells, and also reduced mutation frequencies of UV-irradiated shuttle vector plasmids replicating in XP-A cells. The survival of UV-irradiated cells and mutation frequencies of UV-irradiated plasmids were not completely restored to the unirradiated levels by the removal of CPD. These results suggest that both CPD and other UV damage, probably 6-4PD, can lead to cell killing and mutations.
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PMID:Expression of a mammalian DNA photolyase confers light-dependent repair activity and reduces mutations of UV-irradiated shuttle vectors in xeroderma pigmentosum cells. 1060 16

We investigated the contribution of the xeroderma pigmentosum group C (XPC) gene to DNA repair. We stably transfected XPC cells (XP4PA-SV-EB) with XPC cDNA and selected a partially corrected (XP4PA-SE1) and a fully corrected (XP4PA-SE2) clone. Cell survival after UVC (254 nm) exposure was low for XP4PA-SV-EB, intermediate for XP4PA-SE1, and normal for XP4PA-SE2 cells. XP4PA-SV-EB cells had undetectable XPC mRNA and protein levels. XP4PA-SE1 cells had 130% of normal mRNA but 25% of normal protein levels, whereas XP4PA-SE2 cells had an 18-fold mRNA overexpression and normal XPC protein levels compared with normal cells. We measured cyclobutane pyrimidine dimers (CPD) and 6-4 photoproducts (6-4PP) by using specific mAbs and the ELISA technique. XP4PA-SV-EB cells had no detectable removal of CPD or 6-4PP from their global genome by 24 h after 30 J/m(2) UVC exposure. The partially corrected XP4PA-SE1 cells had normal repair of CPD but minimal repair of 6-4PP by 24 h, whereas the fully corrected XP4PA-SE2 cells regained normal CPD and 6-4PP repair capacities. We also exposed pRSVcat plasmid to UVC (to induce CPD and 6-4PP), to UVC + photolyase (to leave only 6-4PP on the plasmid), or to UVB + acetophenone (to induce only CPD). Host cell reactivation of UVB + acetophenone-, but not of UVC + photolyase-treated plasmids was normal in XP4PA-SE1 cells. Thus, increasing XPC gene expression leads to selective repair of CPD in the global genome. Undetectable XPC protein is associated with no repair of CPD or 6-4PP, detectable but subnormal XPC protein levels reconstitute CPD but not 6-4PP repair, and normal XPC protein levels fully reconstitute both CPD and 6-4PP repair.
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PMID:The xeroderma pigmentosum group C gene leads to selective repair of cyclobutane pyrimidine dimers rather than 6-4 photoproducts. 1068 31

The role of UV light-induced photoproducts in initiating base substitution mutation in human cells was examined by determining the frequency and spectrum of mutation in a supF tRNA gene in a shuttle vector plasmid transfected into DNA repair deficient cells (xeroderma pigmentosum complementation group A). To compare the role of two major UV-induced photoproducts, cis-syn cyclobutane-type pyrimidine dimers (CPDs) and pyrimidine (6-4) pyrimidone photoproducts (6-4PPs), each photoproduct was removed from UV-irradiated plasmid by photoreactivation before transfection. Removal of either CPDs or 6-4PPs by in vitro photoreactivation reduced the mutation frequency while keeping the mutation distribution and the predominance of G:C-A:T transitions as UV-irradiated plasmid without photoreactivation, indicating that both cytosine-containing CPDs and 6-4PPs were premutagenic lesions for G:C-A:T transitions. On the other hand, A:T-G:C transitions were not recovered from plasmids after the removal of 6-4PPs, whereas this type of mutation occurred at a significant level (11%) after the removal of CPDs. Thus, the premutagenic lesions for the A:T-G:C transition are 6-4PPs. Removal of both CPDs and 6-4PPs resulted in the disappearance of mutational hot spots and random distribution of mutation as observed in unirradiated control plasmids. However, the mutational spectrum of photoreactivated plasmids differed significantly from that of unirradiated plasmids. A characteristic feature is a high portion of A:T-T:A transversions (11%) in the photoreactivated plasmid. This mutation is due to nondipyrimidinic "minor" photoproducts, and the mutation spectrum suggests that TA*, the major photoproduct of thymidylyl-(3'-5')-deoxyadenosine, is the premutagenic lesion for this mutation. This is the first report revealing the distinct mutagenic roles of the major UV photoproducts and "minor" photoproducts by the use of (6-4)photolyase.
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PMID:Respective roles of cyclobutane pyrimidine dimers, (6-4)photoproducts, and minor photoproducts in ultraviolet mutagenesis of repair-deficient xeroderma pigmentosum A cells. 1074 46

Exposure to UVB results in formation of cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts in DNA. These can be quantified by a variety of techniques including alkaline gel electrophoresis, ELISAs, Southwestern blotting, and immunohistochemistry. Damage to DNA results in activation of damage response pathways, as indicated by Western blotting using antibodies specific for p53 and breast cancer-associated gene 1 (BRCA1) phosphorylation. The signal from DNA damage to activation of these response pathways appears to be mediated by FKBP12-rapamycin-associated protein (FRAP), since these phosphorylation events are blocked by rapamycin. UVB-induced DNA damage also leads to induction of immunosuppressive cytokines including tumor necrosis factor alpha (TNF-alpha) and interleukin (IL)-10 in skin. Induction of TNF-alpha by UVB is readily detectable in cultured normal human epidermal keratinocytes (NHEKs) using ELISA, while induction of IL-10 is readily detectable in cultured mouse keratinocytes but not in NHEKs. Induction of DNA damage by liposome-encapsulated HindIII results in induction of immunosuppressive responses similar to UVB. Clinical testing shows that liposome-encapsulated T4 endonuclease V or photolyase stimulates repair of CPDs in the skin of human subjects, and prevents UVB-induced immunosuppression. Stimulation of repair and prevention of immunosuppression have been linked to prevention of skin cancer by liposome-encapsulated T4 endonuclease V in repair-deficient xeroderma pigmentosum patients.
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PMID:Measurement of UVB-Induced DNA damage and its consequences in models of immunosuppression. 1223 Nov 88

One of the major critical factors for cancer proneness is the cell response to DNA damage. In this work, we used human DNA repair deficient cell lines to investigate the responses to ultraviolet irradiation that lead to apoptosis, and the influence of maintaining the cells resting in confluent state. UV-induced apoptosis is prevented in photolyase-proficient HeLa cells when cyclobutane pyrimidine dimers (CPDs) are removed by photorepair. At the same time, we show recovery of RNA synthesis, thus indicating that blockage of RNA transcription may trigger apoptosis in human cells. On the other hand, confluent primary XPC and trichothiodystrophy (TTD)/XPD cell lines, related to xeroderma pigmentosum and trichothiodystrophy repair syndromes, had a reduced and delayed apoptosis when compared to non-confluent cells. In contrast, XPA cells were similarly sensitive in both the confluent and non-confluent growing state. The effect of cellular confluence on UV-mediated apoptosis in CSB cells, related to Cockayne's syndrome, was unclear. Thus, these results indicate that the induction of apoptosis by UV light may also be affected by DNA replication. In addition, they argue for the use of confluent primary cells in studies of induction of apoptosis by UV, a condition close to skin cells in vivo.
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PMID:Effect of cell confluence on ultraviolet light apoptotic responses in DNA repair deficient cells. 1464 17

The nucleotide excision repair (NER) system consists of two sub-pathways, global genome repair (GGR) and transcription-coupled repair (TCR), which exhibit distinct functions in the cellular response to genotoxic stress. Defects in TCR result in prolonged UV light-induced stalling of RNA polymerase II and hypersensitivity to apoptosis induced by UV and certain chemotherapeutic drugs. Here, we show that low doses of UV trigger delayed activation of the stress-induced MAPkinase JNK and its proapoptotic targets c-Jun and ATF-3 in TCR-deficient primary human fibroblasts from Xeroderma Pigmentosum (XP) and Cockayne syndrome (CS) patients. This delayed activation of the JNK pathway is not observed in GGR-deficient TCR-proficient XP cells, is independent of functional p53, and is established through repression of the JNK-phosphatase MKP-1 rather than by activation of the JNK kinases MKK4 and 7. Enzymatic reversal of UV-induced cyclobutane pyrimidine dimers (CPDs) by CPD photolyase abrogated JNK activation, MKP-1 repression, and apoptosis in TCR-deficient XPA cells. Ectopic expression of MKP-1 inhibited DNA-damage-induced JNK activity and apoptosis. These results identify both MKP-1 and JNK as sensors and downstream effectors of persistent DNA damage in transcribed genes and suggest a link between the JNK pathway and UV-induced stalling of RNApol II.
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PMID:DNA damage in transcribed genes induces apoptosis via the JNK pathway and the JNK-phosphatase MKP-1. 1604 58

Ultraviolet (UV) light generates two major DNA lesions: cyclobutane pyrimidine dimers (CPDs) and pyrimidine-(6-4)-pyrimidone photoproducts (6-4PPs), but the specific participation of these two lesions in the deleterious effects of UV is a longstanding question. In order to discriminate the precise role of unrepaired CPDs and 6-4PPs in UV-induced responses triggering cell death, human fibroblasts were transduced by recombinant adenoviruses carrying the CPD-photolyase or 6-4PP-photolyase cDNAs. Both photolyases were able to prevent UV-induced apoptosis in cells deficient for nucleotide excision repair (NER) to a similar extent, while in NER-proficient cells UV-induced apoptosis was prevented only by CPD-photolyase, with no effects observed when 6-4PPs were removed by the specific photolyase. These results strongly suggest that both CPDs and 6-4PPs contribute to UV-induced apoptosis in NER-deficient cells, while in NER-proficient cells, CPDs are the only lesions responsible for UV-killing, probably due to the rapid repair of 6-4PPs by NER. As a consequence, the difference in skin photosensitivity, including carcinogenesis, of most of the xeroderma pigmentosum patients and of normal people is probably not only a quantitative aspect, but depends on the type of DNA damage induced by sunlight and its rate of repair.
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PMID:CPDs and 6-4PPs play different roles in UV-induced cell death in normal and NER-deficient human cells. 1809 46

Xeroderma pigmentosum (XP) is a hereditary autosomal recessive disorder characterized by photo hypersensitivity of sun exposed tissues and subsequent several-fold increased risk for malignant changes resulting from impaired ability to repair UV-induced DNA damage. Estimated incidences vary from 1 in 20,000 in Japan to 1 in 250,000 in the USA, and approximately 2.3 per million live births in Western Europe. Diagnosis is made clinically by the presence of unusual sunburns or lentiginosis or onset of cancers at an early age. It is confirmed by cellular tests for defective DNA repair. Although there is no cure for XP as of now, skin problems can be ameliorated with the use of sunscreens, sun avoidance methods, and recurrent tumor excisions. Oral isotretinoin and topical application of 5-fluorouracil to treat actinic keratoses are other therapeutic options. T4N5 and photolyase liposomal lotions are innovations in the therapy of XP. Genetic counselling implicating the effect of consanguineous marriages should be considered in the management of XP patients.
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PMID:Xeroderma pigmentosum: man deprived of his right to light. 2445 35


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