Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0043346 (xeroderma pigmentosum)
 2,924 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The protective role of the skin is provided by the two major compartments of the skin, dermis and epidermis. Both are affected in the long term by consequences of sun exposure such as skin photoaging and cancer development. Characterization of UV-induced skin response at cellular and molecular levels is needed for prevention or correction of these long term effects. The human skin reconstructed in vitro, comprising both a living dermal equivalent and a fully differentiated epidermis represents a predictive tool to characterize wavelength and cell type specific biological damage together with tissular distribution. While UVB directly affects epidermis, inducing DNA lesions and apoptotic sunburn keratinocytes, UVA radiation can directly target the dermal compartment through ROS generation, dermal fibroblasts alterations and extracellular matrix (ECM) modifications. Interactions between the two compartments have also been found, especially for MMP1 induction. In the normal population, photodamage can be repaired through specialized systems. Using skin cells from Xeroderma pigmentosum (XP, a photosensitive and cancer-prone disease), a DNA-repair deficient skin has been developed in vitro. Specific features due to intrinsic XP cell phenotype have been discovered, some of them being indicative of early steps of neoplasia and suggesting a particular role for stroma-epithelium interactions. Finally, human reconstructed skin can be used for approaches designed to regenerate photodamaged skin. The dermal-epidermal junction (DEJ), which is crucial for skin cohesion, is drastically altered in photo-aged skin. The three-dimensional skin model allowed to visualize the improving effects of vitamin C on the DEJ. Modified skin models, lacking one cell type, allowed us to determine the cellular origin of the different markers, their spatial localization, and the respective roles and interactions of keratinocytes and fibroblasts during DEJ formation. All together these studies give a global and tissular view concerning the effects of UV light on skin cells and emphazise the interest of such models for general aspects of cellular biology. By allowing the control of cells used to reconstruct the model and their origin, these studies make it possible to assess the respective role of the two major cellular actors of the skin as well as their interactions. Ongoing research about incorporating other cell types may certainly give rise to even more relevant models.
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PMID:[Human skin reconstructed in vitro as a model to study the keratinocyte, the fibroblast and their interactions: photodamage and repair processes]. 1673 25

Xeroderma pigmentosum type C (XPC) is a rare autosomal recessive disorder that occurs due to inactivation of the XPC protein, an important DNA damage recognition protein involved in DNA nucleotide excision repair (NER). This defect, which prevents removal of a wide array of direct and indirect DNA lesions, is associated with a decrease in catalase activity. To test the hypothesis of a novel photoprotective approach, we irradiated epidermis reconstructed with XPC human keratinocytes sustainably overexpressing lentivirus-mediated catalase enzyme. Following UVB irradiation, there was a marked decrease in sunburn cell formation, caspase-3 activation and p53 accumulation in human XPC-reconstructed epidermis overexpressing catalase. Moreover, XPC-reconstructed epidermis was more resistant to UVB-induced apoptosis than normal reconstructed epidermis. While not correcting the gene defect, indirect gene therapy using antioxidant enzymes may be of help in limiting photosensitivity in XPC and probably in other monogenic/polygenic photosensitive disorders characterized by ROS accumulation.
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PMID:Catalase overexpression reduces UVB-induced apoptosis in a human xeroderma pigmentosum reconstructed epidermis. 1820 16

Arsenic exerts its cytotoxicity via the generation of reactive oxygen species and inhibition of DNA repair. How arsenic disturbs oxidative DNA damage repair is, however, unclear. We found that arsenic trioxide (ATO), like ultraviolet (UV) irradiation, induced the expression of xeroderma pigmentosum group C (XPC) but not of xeroderma pigmentosum A in a human glioma cell line, U87. To explore the role of XPC in the toxic effects of ATO, small interfering RNA was used to silence XPC (siXPC) in U87 cells. siXPC cells were more susceptible to UV irradiation and ATO-induced cell death than control cells. Increased siXPC cell death induced by ATO was accompanied by increased senescence and autophagy. Because increased DNA strand breaks in siXPC cells were observed only when cells were concomitantly treated with ATO and DNA repair inhibitors, XPC silencing apparently did not interfere with repair of ATO-induced DNA damage. Although intracellular ROS levels were not significantly enhanced in siXPC cells, ATO treatment did result in increased 8-hydroxy-2'-deoxyguanosine and hyperoxidized peroxiredoxin. Enhanced superoxide production and autophagy by ATO in siXPC cells were suppressed by co-incubation with N-acetylcysteine (NAC). Furthermore, XPC silencing caused decreased glutathione levels and increased catalase and Mn-superoxide dismutase activities. Increased catalase activity in siXPC cells was suppressed by ATO treatment. XPC silencing also enhanced reporter activity of activator protein-1, whereas enhanced activity was suppressed by NAC. Taken together, our results indicate that XPC silencing causes increased ATO susceptibility by disturbing redox homeostasis rather than reducing DNA repair.
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PMID:XPC silencing sensitizes glioma cells to arsenic trioxide via increased oxidative damage. 2040 67

DNA damage is a well-known initiator of tumorigenesis. Studies have shown that most cancer cells rely on aerobic glycolysis for their bioenergetics. We sought to identify a molecular link between genomic mutations and metabolic alterations in neoplastic transformation. We took advantage of the intrinsic genomic instability arising in xeroderma pigmentosum C (XPC). The XPC protein plays a key role in recognizing DNA damage in nucleotide excision repair, and patients with XPC deficiency have increased incidence of skin cancer and other malignancies. In cultured human keratinocytes, we showed that lentivirus-mediated knockdown of XPC reduced mitochondrial oxidative phosphorylation and increased glycolysis, recapitulating cancer cell metabolism. Accumulation of unrepaired DNA following XPC silencing increased DNA-dependent protein kinase activity, which subsequently activated AKT1 and NADPH oxidase-1 (NOX1), resulting in ROS production and accumulation of specific deletions in mitochondrial DNA (mtDNA) over time. Subcutaneous injection of XPC-deficient keratinocytes into immunodeficient mice led to squamous cell carcinoma formation, demonstrating the tumorigenic potential of transduced cells. Conversely, simultaneous knockdown of either NOX1 or AKT1 blocked the neoplastic transformation induced by XPC silencing. Our results demonstrate that genomic instability resulting from XPC silencing results in activation of AKT1 and subsequently NOX1 to induce ROS generation, mtDNA deletions, and neoplastic transformation in human keratinocytes.
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PMID:XPC silencing in normal human keratinocytes triggers metabolic alterations that drive the formation of squamous cell carcinomas. 2112 41

Although the developmental stages of gastric carcinoma are still not clear, the constantly generated reactive oxygen and nitrogen species (ROS/RNS) may contribute to the process of carcinogenesis by interacting with DNA. 8-oxoguanine DNA glycosylase-1 (OGG1) is an enzyme involved in base excision repair of 8-oxoguanine that is one of the premutagenic lesions generated by ROS in DNA. The bulky adducts, are recognized and repaired by nucleotid excision repair (NER) enzymes, including xeroderma pigmentosum C and D (XPC, XPD). Eligible 106 gastric cancer patients and 116 cancer-free individuals constituted the study and control groups, respectively. Association between OGG1 Ser326Cys, XPC Lys939Gln, XPD Lys751Gln polymorphisms and the susceptibility tho cancer and the oxidative stress status were evaluated. DNA was extracted from peripheral blood cells and genotypes were determined by using PCR-RFLP. Serum nitric oxide, albumin concentrations, total antioxidant status and Helicobacter pylori IgG were determined. Serum albumin and nitric oxide of cancer patients were lower than that of the controls (P < 0.05). None of the evaluated polymorphisms or Helicobacter pylori IgG seropositivity associated with increased risk of gastric cancer, despite of the increased oxidative stress in cancer patients.
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PMID:DNA repair enzyme polymorphisms and oxidative stress in a Turkish population with gastric carcinoma. 2139 May 2

Xeroderma Pigmentosum (XP) is a DNA repair disease characterized by nucleotide excision repair (NER) malfunction, leading to photosensitivity and increased incidence of skin malignancies. The role of XP-A in NER pathways has been well studied while discrepancies associated with ROS levels and the role of radical species between normal and deficient XPA cell lines have been observed. Using liquid chromatography tandem mass spectrometry we have determined the four 5',8-cyclopurines (cPu) lesions (i.e., 5'R-cdG, 5'S-cdG, 5'R-cdA and 5'S-cdA), 8-oxo-dA and 8-oxo-dG in wt (EUE-pBD650) and XPA-deficient (EUE-siXPA) human embryonic epithelial cell lines, under different oxygen tension (hyperoxic 21%, physioxic 5% and hypoxic 1%). The levels of Fe and Cu were also measured. The main findings of our study were: (i) the total amount of cPu (1.82-2.52 lesions/106 nucleotides) is the same order of magnitude as 8-oxo-Pu (3.10-4.11 lesions/106 nucleotides) in both cell types, (ii) the four cPu levels are similar in hyperoxic and physioxic conditions for both wt and deficient cell lines, whereas 8-oxo-Pu increases in all cases, (iii) both wt and deficient cell lines accumulated high levels of cPu under hypoxic compared to physioxic conditions, whereas the 8-oxo-Pu levels show an opposite trend, (iv) the diastereoisomeric ratios 5'R/5'S are independent of oxygen concentration being 0.29 for cdG and 2.69 for cdA for EUE-pBD650 (wt) and 0.32 for cdG and 2.94 for cdA for EUE-siXPA (deficient), (v) in deficient cell lines Fe levels were significantly higher. The data show for the first time the connection of oxygen concentration in cells with different DNA repair ability and the levels of different DNA lesions highlighting the significance of cPu. Membrane lipidomic data at 21% O2 indicated differences in the fatty acid contents between wild type and deficient cells, envisaging functional effects on membranes associated with the different repair capabilities, to be further investigated.
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PMID:Purine DNA Lesions at Different Oxygen Concentration in DNA Repair-Impaired Human Cells (EUE-siXPA). 3168 70