Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Xeroderma pigmentosum (XP) and trichothiodystrophy (TTD) are two recessively transmitted human diseases characterized by DNA repair deficiency. While XP is associated with a very high incidence of cancer on skin exposed to sunlight, TTD is not a cancer-prone disease. Therefore, unrepaired UV-induced DNA lesions do not appear to be enough to give rise to tumors. In order to understand the differences between these two syndromes, we measured catalase activity in cellular extracts, UV irradiated or not, and quantified H2O2 production following in vitro UV irradiation. We confirmed on 21 different XP diploid fibroblast lines that catalase activity was decreased on average by a factor of five as compared to controls, while XP heterozygote lines exhibited intermediary responses. All seven TTD lines we tested were deficient in UV-induced lesion repair and exhibited a high level of catalase activity. However, molecular analysis of catalase transcription showed no difference between normal, XP and TTD cell lines. This was confirmed by Western blots where the amount of catalase subunits was identical in all cell lines studied. Finally, UV irradiation induces five and three times more H2O2 production in XP lines compared with TTD or controls respectively. These striking differences between TTD and XP indicate that UV light, directly or indirectly, together with defective oxidative metabolism may increase the initiation and/or the progression steps in the XP environment compared to TTD. This may partly explain the different tumoral phenotype observed between the two diseases.
Carcinogenesis 1992 Mar
PMID:Striking differences in cellular catalase activity between two DNA repair-deficient diseases: xeroderma pigmentosum and trichothiodystrophy. 154 19

DNA repair in mammals consists of a large family of genes that encode a variety of mutually interacting gene products. These gene products coordinately locate and prepare damaged sites in chromatin for eventual excision and replacement and interact with transcriptionally active and replicating regions. Subsets of repair genes are represented by the complementation groups of xeroderma pigmentosum (XP), Cockayne syndrome, trichothiodystrophy and the ERCC series, which overlap one another to varying degrees. Cloned DNA sequences or whole chromosomes correct the UV-sensitive phenotype of XP by only 6-50%, which may be informative for the precise mechanisms of complementation and repair and for the relative importance of various UV photoproducts. Repair deficiencies in vivo are associated with increases in the toxic effects of UV damage and chronic expression of damage-inducible genes, with consequent implications for viability, development, neurological and immunological function, and carcinogenesis.
Carcinogenesis 1990 Jun
PMID:Do we know the cause of xeroderma pigmentosum? 218 96

Nucleotide excision repair (NER)-deficient human cells have been assigned so far to a genetic complementation group by a somatic cell fusion assay and, more recently, by microinjection of cloned DNA repair genes. We describe a new technique, based on the host cell reactivation assay, for the rapid determination of the complementation group of NER-deficient xeroderma pigmentosum (XP), Cockayne's syndrome (CS) and photosensitive trichothiodystrophy (TTD) human cells by cotransfection of a UV-irradiated reporter plasmid with a second vector containing a cloned repair gene. Expression of the reporter gene, either chloramphenicol acetyltransferase (CAT) or luciferase, reflects the DNA repair ability restored by the introduction of the appropriate repair gene. All genetically characterized XP, CS and TTD/XP-D cells tested failed to express the UV-irradiated reporter gene, this reflecting their NER deficiency whereas cotransfection with the repair plasmid expressing a gene specific for the given complementation group increased the enzyme activity to the level reached by normal cells. Selective recovery of both reporter enzyme activities was observed after cotransfection with the XPC gene for the XP17VI cells and with the XPA gene for both XP18VI and XP19VI cells. Using this method, we assigned three new NER-deficient human cells obtained from patients presenting clinical symptoms described as classical XP to either XP group A (XP18VI and XP19VI) and XP group C (XP17VI). Therefore, this technique increases the range of methods now available to determine the complementation group of new NER deficient patients with the advantage, unlike the somatic cell fusion assay or the microinjection procedure, of being simple, rapid, and inexpensive.
Carcinogenesis 1995 May
PMID:Development of a new easy complementation assay for DNA repair deficient human syndromes using cloned repair genes. 776 57

Xeroderma pigmentosum, Cockayne syndrome, the xeroderma pigmentosum-Cockayne syndrome complex, and trichothiodystrophy cells have defects in DNA repair and are associated with clinical and cellular hypersensitivity to ultraviolet radiation (UV). Familial dysplastic nevus syndrome cells have UV hypermutability. Although xeroderma pigmentosum and dysplastic nevus syndrome have markedly increased cancer risk. Cockayne syndrome and trichothiodystrophy do not. At the molecular level, these disorders are associated with several different genetic defects as evidenced by the existence of multiple overlapping complementation groups. Recent progress has been made in identifying the chromosomal location and cloning the defective genes in these disorders. Using plasmid shuttle vectors we have shown abnormal repair and mutagenesis of DNA damaged by 254-nm (UVC) or 295-nm (UVB) radiation or the chemical carcinogen aflatoxin in cells from patients with xeroderma pigmentosum. Although xeroderma pigmentosum cells are defective in repair of all photoproducts, Cockayne syndrome cells appear to be defective in repair of cyclobutane dimers and have normal repair of nondimer photoproducts. DNS cells have post UV plasmid hypermutability. These diseases may serve as models for examining molecular mechanisms of carcinogenesis in humans.
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PMID:Xeroderma pigmentosum and related disorders: examining the linkage between defective DNA repair and cancer. 796 92

Trichothiodystrophy (TTD) is a rare genetic disease with heterogeneous clinical features associated with specific deficiencies in nucleotide excision repair. Patients have brittle hair due to a reduced content of cysteine-rich matrix proteins. About 50% of the cases reported in the literature are photosensitive. In these patients an altered cellular response to UV, due to a specific deficiency in nucleotide excision repair, has been observed. The majority of repair-defective TTD patients have been assigned by complementation analysis to group D of xeroderma pigmentosum (XP). Recently, the human excision repair gene ERCC2 has been shown to correct the UV sensitivity of XP-D fibroblasts. In this work we describe the effect of ERCC2 on the DNA repair deficient phenotype of XP-D and on two repair-defective TTD cell strains (TTD1VI and TTD2VI) assigned by complementation analysis to group D of XP. ERCC2 cDNA, cloned into a mammalian expression vector, was introduced into TTD and XP fibroblasts via DNA-mediated transfection or microneedle injection. UV sensitivity and cellular DNA repair properties, including unscheduled DNA synthesis and reactivation of a UV-irradiated plasmid containing the chloramphenicol acetyltransferase reporter gene (pRSVCat), were corrected to wild-type levels in both TTD and XP-D cells. These data show that a functional ERCC2 gene is sufficient to reestablish a wild-type DNA repair phenotype in TTD1VI and TTD2VI cells, confirming the genetic relationship between TTD and XP-D. Furthermore, our findings suggest that mutations at the ERCC2 locus are responsible for causing a similar phenotype in TTD and XP-D cells in response to UV irradiation, but produce quite different clinical symptoms.
Carcinogenesis 1994 Aug
PMID:Correction by the ERCC2 gene of UV sensitivity and repair deficiency phenotype in a subset of trichothiodystrophy cells. 805 25

Trichothiodystrophy (TTD) is a rare genetic disease associated in approximately 50% of patients with DNA repair deficiency analogous to that found in xeroderma pigmentosum group D (XP-D) patients. Although XP-D patients exhibit a very high level of skin cancer on sun-exposed parts, TTD is not associated with cancer. We analysed UV-induced mutations in TTD cells and compared them to data in XP-D in order to determine if the molecular mechanisms of mutagenesis can explain the discrepancies between these two syndromes. We first immortalized a fibroblast TTD line with an ori(-)-SV40 plasmid. To investigate the kinds of mutations induced in TTD cells, we used an UV-irradiated (at 254 nm) shuttle vector carrying the supF tRNA gene as a target. We compared our data with those published by others with the same pZ189 vector in normal and XP-D fibroblast lines (Bredberg et al., Proc. Natl. Acad. Sci. USA, 83, 8273-8277; Seetharam et al., J. Clin. Invest., 80, 1613-1617). The frequency of mutants increased linearly with UV dose and the slope was > 4 times steeper in TTD cells than that observed in normal cells. The mutation frequency was almost identical between XP-D and TTD cells. Sequence analysis of the supF tRNA gene showed that 96% of mutations obtained in TTD cells are base substitutions. Single base substitutions were found in 62% of mutants in TTD cells while they corresponded to 86% in XP-D cells. The frequency of multiple mutations in TTD cells (26%) was similar to that in normal cells (27%) and much higher than that in XP-D cells (9%). Despite the fact that the same gene is mutated in TTD and XP patients, the molecular characteristics of mutagenesis are not identical. The fact that the frequency of mutations in TTD and XP cells are similar shows that a high level of UV-induced mutations is therefore not always directly related to cancer-proneness. Other factors such as catalase activity and immuno-surveillance may intervene in cancer incidence.
Carcinogenesis 1993 Jul
PMID:UV-induced mutations in a shuttle vector replicated in repair deficient trichothiodystrophy cells differ with those in genetically-related cancer prone xeroderma pigmentosum. 839 42

Trichothiodystrophy (TTD) is a rare autosomal recessive disease characterized by brittle hair with reduced sulfur content, mental and physical retardation, a peculiar face and ichthyosis. Photosensitivity has been reported in approximately 20% of the cases in the literature. DNA repair investigations demonstrated that clinical photosensitivity is usually associated with an enhancement of the cellular UV-sensitivity and that the repair defect is in the same gene as in patients from group D of xeroderma pigmentosum (XP). In this paper we describe the characterization of 13 further TTD patients; a defect in the nucleotide-excision repair was observed in fibroblast strains from 10 patients, confirming that TTD is frequently associated with DNA repair defects. Genetic analysis based on complementation studies demonstrated the presence of the XP-D defect in seven repair-defective TTD cases, indicating definitively that the concurrence of TTD with XP-D is not a sporadic or casual event. However, three further cell strains (TTD4VI and TTD6VI from two French siblings and TTD1BR from an English patient) showed restoration of normal UV-induced DNA repair synthesis after fusion with XP or TTD cells belonging to XP group D. These observations, which give the first indication that TTD is associated with repair defects behaving differently in the functional test of complementation, suggest some kind of causal connection between defective excision-repair factors and clinical features diagnostic for TTD. A peculiar aspect of TTD in which repair deficiencies are not related to an increased susceptibility to cancer is confirmed also in all the repair-defective TTD patients investigated in this paper.
Carcinogenesis 1993 Jun
PMID:Genetic heterogeneity of the excision repair defect associated with trichothiodystrophy. 850 95

Patients with xeroderma pigmentosum (XP), a DNA repair disorder, run a large risk of developing skin cancer in sun-exposed areas. Cancer proneness in these patients correlates with a mammalian SOS-like response, "enhanced reactivation (ER) of viruses." Here, we report that radiation-induced activation of the ornithine decarboxylase (ODC) gene, a putative proto-oncogene, is required for this response. Various diploid fibroblast strains derived from a non-cancer-prone subclass of XP patients, which lack the ER response, were irradiated with 2 J/m2 and assessed for gene induction. In these fibroblasts, an absence of induction of ODC by UV-C was observed at the levels of mRNA, protein, and enzyme activity. This lack of induction is quite specific because the genes for fos and collagenase were induced as they were in normal XP cells. The apparent linkage between non-cancer proneness and a lack of ER and ODC induction was confirmed in a fibroblast strain derived from a patient with another DNA repair disorder, trichothiodystrophy, which does not lead to cancer proneness: in these cells, no induction of the ER response nor of ODC occurs after UV-C irradiation. Repair deficiency, however, is not essential because the simultaneous lack of ODC and ER induction after 10 J/m2 UV-C was found in at least one repair-proficient fibroblast. Next, a specific inhibitor of ODC, difluoromethylornithine, at a dose of 10 mM, completely blocked the ER response in cultured normal skin fibroblasts, suggesting that the ODC enzyme is in fact essential for the ER response. Difluoromethylornithine, although it did not affect other processes such as DNA repair, leads to a block in the cell division cycle at the G1-S transition. Interestingly, other blockers of this transition, wortmannin (500 nM) and mimosine (100 mM), also decreased the ER response. Finally, the ER and ODC responses also seem to be linked after treatment with X-irradiation (3 Gy), suggesting that both are part of a general response to DNA damage, at least in human skin fibroblasts. Apart from the abnormal ER and ODC responses, fibroblasts from non-tumor-prone XP patients react in the same way to radiation as do fibroblasts from tumor-prone XP patients with respect to other parameters. Thus, the lack of ODC induction after radiation may help to protect XP patients against skin carcinogenesis.
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PMID:A lack of radiation-induced ornithine decarboxylase activity prevents enhanced reactivation of herpes simplex virus and is linked to non-cancer proneness in xeroderma pigmentosum patients. 933 Nov 2

Among the major responses of human cells to DNA damage is accumulation of the p53 tumor suppressor protein, which plays a crucial role as a cell-cycle checkpoint. We have already shown that this response is different in cells from the UV-hypersensitive human syndromes xeroderma pigmentosum (XP) and trichothiodystrophy (TTD), which overlap with each other and arise from mutations in genes involved in nucleotide excision repair. In this paper we report that correction of the repair defect by retroviral-mediated transduction of the wild-type XPD gene in XP-D and TTD/XP-D untransformed primary fibroblasts leads to a normal p53 response in these cells. Thus, the complemented cells, like normal human fibroblasts, require higher UV doses (10 J/m2) for p53 induction than the parental repair-deficient XP-D or TTD/XP-D cells (both mapping at the XPD locus), which accumulate p53 protein at very low UV doses (2.5 and 5 J/m2). The p53 protein levels return to normal 24 h after irradiation when UV-induced lesions have been efficiently repaired by the restored NER activity. These data confirm our earlier results that p53 accumulation following UV treatment is directly related to the presence of unrepaired cyclobutane dimers on the transcribed strand of active genes.
Carcinogenesis 1998 Sep
PMID:Recovery of the normal p53 response after UV treatment in DNA repair-deficient fibroblasts by retroviral-mediated correction with the XPD gene. 977 45

Patients with the nucleotide excision repair (NER) disorder xeroderma pigmentosum (XP) are highly predisposed to develop sunlight-induced skin cancer, in remarkable contrast to photosensitive NER-deficient trichothiodystrophy (TTD) patients carrying mutations in the same XPD gene. XPD encodes a helicase subunit of the dually functional DNA repair/basal transcription complex TFIIH. The pleiotropic disease phenotype is hypothesized to be, in part, derived from a repair defect causing UV sensitivity and, in part, from a subtle, viable basal transcription deficiency accounting for the cutaneous, developmental, and the typical brittle hair features of TTD. To understand the relationship between deficient NER and tumor susceptibility, we used a mouse model for TTD that mimics an XPD point mutation of a TTD patient in the mouse germline. Like the fibroblasts from the patient, mouse cells exhibit a partial NER defect, evident from the reduced UV-induced DNA repair synthesis (residual repair capacity approximately 25%), limited recovery of RNA synthesis after UV exposure, and a relatively mild hypersensitivity to cell killing by UV or 7,12-dimethylbenz[a]anthracene. In accordance with the cellular studies, TTD mice exhibit a modestly increased sensitivity to UV-induced inflammation and hyperplasia of the skin. In striking contrast to the human syndrome, TTD mice manifest a dear susceptibility to UV- and 7,12-dimethylbenz[a]anthracene-induced skin carcinogenesis, albeit not as pronounced as the totally NER-deficient XPA mice. These findings open up the possibility that TTD is associated with a so far unnoticed cancer predisposition and support the notion that a NER deficiency enhances cancer susceptibility. These findings have important implications for the etiology of the human disorder and for the impact of NER on carcinogenesis.
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PMID:Mouse model for the DNA repair/basal transcription disorder trichothiodystrophy reveals cancer predisposition. 1041 15


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