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Enhancement of XPG mRNA expression by human interferon- in Cockayne syndrome cells
... Notably, both RSa and KT cells also show high sensitivity to cell proliferation inhibition by human interferon-β (HuIFN-β) (3). Coordination between cellular sensitivity to UVC and HuIFN was observed in various human cell lines, but the mechanisms underlying the coordination remain unclear (4)(5)(6). However, cellular chaperone metabolism may be the key for clarifying these mechanisms. ...
... However, cellular chaperone metabolism may be the key for clarifying these mechanisms. Notably, UVC-sensitive cells, pretreated with HuIFN-β and then irradiated with UVC, become resistant to UVC lethality (5,6); however, the role of the chaperones in the HuIFN-β effect has not been studied. ...
Revealing the key molecules regulating the stress-response pathways in human cells is an intriguing problem. Chaperones, such as glucose-regulated protein 78 (GRP78) and heat shock protein 27 (HSP27), are important molecules for protecting the viability of human cells; however, it remains to be further clarified whether the molecules differentially modulate cellular responses to various types of stressors, such as DNA-damaging ultraviolet ray C (principally 254-nm wavelength, UVC) and cytocidal cytokine interferons. In the present study, the human breast cancer cell lines KT and MCF-7 were examined for GRP78 and HSP27 expression following exposure to UVC and human interferon-β (HuIFN-β). The KT cells demonstrated a higher sensitivity to both UVC and HuIFN-β lethality than MCF-7 cells. The cellular expression levels of GRP78 in KT cells, assessed by western blot analysis, were approximately 2-fold higher than that in MCF-7 cells, while the expression of HSP27 in the KT cells was 20% of the expression in the MCF-7 cells. Decreased resistance to UVC lethality was observed in GRP78 siRNA-transfected KT cells. In addition, HSP27 cDNA transfection of KT cells resulted in an increased resistance to UVC lethality. The cDNA-transfected KT cells showed an increased viability against HuIFN-β, compared with that of empty vector-transfected cells. By contrast, KT cells pretreated with HuIFN-β and irradiated with UVC demonstrated an increased resistance to UVC lethality, in association with increased levels of HSP27 expression. Thus, HSP27 may control the survival response pathways to both UVC and HuIFN-β in the human cells examined.
Ultraviolet (UV) radiation from sunlight is a major etiologic factor for skin cancer, the most prevalent cancer in the U.S., as well as premature skin aging. In particular, UVB radiation causes formation of specific DNA damage photoproducts between pyrimidine bases. These DNA damage photoproducts are repaired by a process called nucleotide excision repair, also known as UV-induced DNA repair. When left unrepaired, UVB-induced DNA damage leads to accumulation of mutations, predisposing people to carcinogenesis as well as to premature aging. Genetic loss of nucleotide excision repair leads to severe disorders, namely, xeroderma pigmentosum (XP), trichothiodystrophy (TTD) and Cockayne syndrome (CS), which are associated with predisposition to skin carcinogenesis at a young age as well as developmental and neurological conditions. Regulation of nucleotide excision repair is an attractive avenue to preventing or reversing these detrimental consequences of impaired nucleotide excision repair. Here we review recent studies on molecular mechanisms regulating nucleotide excision repair by extracellular cues and intracellular signaling pathways, with a special focus on the molecular regulation of individual repair factors. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
DNA repair is the first barrier in the defense against genotoxic stress. In recent years, mechanisms that recognize DNA damage and activate DNA repair functions through transcriptional upregulation and post-translational modification were the focus of intensive research. Most DNA repair pathways are complex, involving many proteins working in discrete consecutive steps. Therefore, their balanced expression is important for avoiding erroneous repair that might result from excessive base removal and DNA cleavage. Amelioration of DNA repair requires both a fine-tuned system of lesion recognition and transcription factors that regulate repair genes in a balanced way. Transcriptional upregulation of DNA repair genes by genotoxic stress is counteracted by DNA damage that blocks transcription. Therefore, induction of DNA repair resulting in an adaptive response is only visible through a narrow window of dose. Here, we review transcriptional regulation of DNA repair genes in normal and cancer cells and describe mechanisms of promoter activation following genotoxic exposures through environmental carcinogens and anticancer drugs. The data available to date indicate that 25 DNA repair genes are subject to regulation following genotoxic stress in rodent and human cells, but for only a few of them, the data are solid as to the mechanism, homeostatic regulation and involvement in an adaptive response to genotoxic stress.
Unlabelled:
MAIN CLINICAL FEATURES: Xeroderma pigmentosum is a rare, recessive disorder clinically characterized by extreme photosensitivity, pigmented abnormalities of the skin-exposed areas, and frequent ocular and neurological abnormalities. Xeroderma pigmentosum syndrome is associated with an estimated 2000-fold increase in the risk to develop skin cancer (basal cell carcinoma, squamous cell carcinoma and melanoma).
A heterogeneous disease:
Skin or blood cells from Xeroderma pigmentosum patients are hypersensitive to killing by ultraviolet and hypermutable after ultraviolet C treatment Cell fusion experiments based on complementation of repair synthesis have recognized the presence of seven Xeroderma pigmentosum groups which exhibit various defects in the initial steps of the DNA nucleotide excision repair pathway. A variant Xeroderma pigmentosum form has been found to be normal in nucleotide excision repair but abnormal in a poorly to be normal in nucleotide excision repair but abnormal in a poorly understood postreplication repair process.
Pathophysiology:
The Xeroderma pigmentosum complementation groups differ in terms of severity of clinical, cellular and genetic features. Molecular and biochemical studies of the Xeroderma pigmentosum syndrome have led to a better understanding of the mechanisms of ultraviolet-induced sensitivity and the mechanism of cancer development after ultraviolet exposure.
Bisphenol A is used as a monomer in the production of polycarbonate plastic products. The widespread use of bisphenol A has raised concerns about its effects in humans. Since there is little information on the mutagenic potential of the chemical, the mutagenicity of bisphenol A was tested using human RSa cells, which has been utilized for identification of novel mutagens. In genomic DNA from cells treated with bisphenol A at concentrations ranging from 1x10(-7) to 1x10(-5)M, base substitution mutations at K-ras codon 12 were detected using PCR and differential dot-blot hybridization with mutant probes. Mutations were also detected using the method of peptide nucleic acid (PNA)-mediated PCR clamping. The latter method enabled us to detect the mutation in bisphenol A-treated cells at a dose (1x10(-8)M) equivalent to that typically found in the environment. Induction of ouabain-resistant (Oua(R)) phenotypic mutation was also found in cells treated with 1x10(-7) and 1x10(-5)M of bisphenol A. The induction of K-ras codon 12 mutations and Oua(R) mutations was suppressed by pretreating RSa cells with human interferon (HuIFN)-alpha prior to bisphenol A treatment. The cells treated with bisphenol A at the concentration of 1x10(-6)M elicited unscheduled DNA synthesis (UDS). These findings suggested that bisphenol A has mutagenicity in RSa cells as well as mutagens that have been tested in these cells, and furthermore, that a combination of the PNA-mediated PCR clamping method with the human RSa cell line may be used as an assay system for screening the mutagenic chemicals at very low doses.
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