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Patients with ataxia-telangiectasia (AT), a human autosomal recessive genetic disease, are uniformly hypersensitive to ionizing radiation as measured by colony-forming ability and by chromosomal aberrations. Obligate heterozygotes, i.e., parents of AT patients, are slightly more radiosensitive than normal humans in terms of both colony-forming ability and chromosomal aberrations formed in G2. Thus, this system not only furnishes a model system to study factors that are responsible for radioresistance in normal human beings, but is also a unique tool for determining the role of gene dosage on radiation-induced cell killing. Because AT cells seem to be hypomutable to ionizing radiation, they also can be used to study the relationship between radiosensitivity and mutability and, therefore, carcinogenesis. Isolation of the defective gene that causes hypersensitivity in AT cells and its counterpart in normal cells should lead to a breakthrough in our understanding of radiation effects and how they can be prevented in human beings.
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PMID:Ataxia-telangiectasia as a model system for studies of radiation protection mechanisms. 341 Jun 98

The effects of modification of poly(ADP-ribosyl)ation reactions have been examined in normal (F107) and ataxia telangiectasia (AT23) fibroblasts following damage by methyl methanesulphonate (MMS) and u.v. light. The technique of benzoylated DEAE (BD)-cellulose chromatography was utilized to estimate both the extent and nature of the damage to DNA induced by these agents and to examine the effects of an inhibitor of poly(ADP-ribose) synthetase, 3-aminobenzamide (3AB), on these parameters. Single strand breakage, determined by nucleoid sedimentation, and levels of poly ADP(ribose) synthesis were monitored. Increase in the proportion of DNA containing single-stranded regions, as measured by stepwise elution from BD-cellulose, was observed following MMS damage in both cell types. In the presence of 3AB, a further accumulation of DNA containing single-stranded regions occurred, with the effect being more prominent in AT23 fibroblasts. U.v. light damage did not induce increased binding to BD-cellulose in normal cells, and the increase observed in AT23 cells was much less than that seen following alkylation damage. Examination of the nature of single-stranded damage by caffeine gradient elution from BD-cellulose following MMS treatment revealed discrete structural lesions, which were enhanced in the presence of 3AB. A similar effect was exerted by arabinofuranosyl cytosine. The behaviour of these intermediates, which could be associated with repair, was not in accord with the suggestion that 3AB inhibits only the ligation stage of the repair process. Our results suggest that specific intermediate stages in DNA repair are sensitive to 3AB, and it seems likely that these stages occur prior to ligation.
Carcinogenesis 1987 Jan
PMID:Inhibition of poly(ADP-ribose) synthesis may affect DNA repair prior to ligation. 380 93

Cells of patients with ataxia telangiectasia (AT), an inherited disease characterized by a high propensity to cancer, are hypersensitive to ionizing radiation. We investigated whether the hyper-radiosensitivity of AT cells correlated with a defect in their constitutive and/or conditional ability to rescue a damaged exogenous virus. For that purpose, parvovirus H-1, a single-stranded DNA virus whose intranuclear replication mostly relies on host cell functions, was used as a probe. The survival of u.v.- or gamma-irradiated H-1 was measured in X-, u.v.- or mock-irradiated human cells of normal (NB-E) or AT (AT5BIVA) origin. gamma-Irradiated H-1 survived to similar extents in untreated normal and AT cell lines. Both X- and u.v.-irradiation induced normal cells to achieve an enhanced reactivation (ER) of gamma- or u.v.-damaged H-1. In contrast, neither dose-effect curves nor time course revealed significant levels of ER expression after X- or u.v.-irradiation in AT5BIVA cells. Our results suggest that the impairment of ER of damaged parvoviruses may constitute a marker of the AT cell phenotype and be related to the radiosensitivity of AT cells.
Carcinogenesis 1987 Feb
PMID:Deficient expression of enhanced reactivation of parvovirus H-1 in ataxia telangiectasia cells irradiated with X-rays or u.v. light. 380 17

The deoxynucleoside 5'-triphosphate (dNTP) pool sizes have been determined before and after electron (e-) irradiation in sets of radiation sensitive and resistant cell lines. In the L5178Y mouse lymphoma radiosensitive line (LS), the dTTP pool fell 50% following irradiation, whilst the three other dNTP pools remained unaltered. On the other hand, for the radioresistant line (AII) all four dNTP pools increased by 2-to 3-fold. The dNTP pools of the Chinese hamster radiosensitive (V79) line and radioresistant (V79/79) lines were unaltered by the radiation, but a difference in pool size was present before irradiation, with the pools of the V79 cells being approximately twice those of the V79/79 cells. Two out of the three ataxia telangiectasia cell lines studied show reduced dNTP pools when compared with those of normal human fibroblasts and these pools were also unaltered by the radiation. In the L5178Y and Chinese hamster cells the levels of enzymes involved in the biosynthesis of dNTPs have been determined. In general the higher the level of ribonucleoside diphosphate reductase (RDR) the larger the cellular pools. The observed levels of RDR could, in part, explain the observed results. Increasing the dTTP pool by the addition of deoxythymidine and deoxycytidine to the cell culture with the V79/79 cells reduced their sensitivity to the radiation. These results indicate a relationship between a cell's sensitivity to e- irradiation and the sizes of the cellular dNTP pools. However, the exact nature of any such relationship is unknown.
Carcinogenesis 1987 Mar
PMID:The sizes of cellular deoxynucleoside 5'-triphosphate pools in relation to sensitivity to electron irradiation using sensitive and resistant cell lines. 381 36

Ataxia telangiectasia (AT) is a rare human genetic disorder, whose numerous clinical hallmarks include a predisposition to lymphoreticular cancers and a hypersensitivity to conventional radiotherapy. Furthermore, AT cells in vitro exhibit a hypersensitivity to ionising radiation that appears to be correlated with an increased frequency of chromosomal aberrations, a resistance of de novo DNA synthesis to inhibition by radiation-induced DNA damage, a reduced mitotic delay and possible defects in DNA repair. In this study, a sensitive viral assay has been used to investigate the capacity of gamma-irradiated AT cells to support the replication of undamaged virus, as well as the extent to which the survival of radiation-damaged virus was affected by gamma-irradiation of these host cells prior to infection. The expression of such enhanced reactivation (ER) of both u.v.-irradiated (u.v. dose = 1.2 X 10(3) J/m2) and gamma-irradiated (dose = 2 Mrad) adenovirus type 2 (Ad2) was examined in a variety of normal and AT human fibroblast strains. Unirradiated and gamma-irradiated fibroblasts were infected with unirradiated or irradiated Ad2, either immediately or at different times after cell monolayer irradiation, and at 48 h after infection cultures were examined by indirect immunofluorescence to determine the number of cells in which Ad2 viral structural antigen (Vag) was expressed. For immediate infection of normal human fibroblasts, both a decrease in unirradiated virus expression and an increase in ER were observed with increasing gamma-ray dose to the cells. In contrast, AT fibroblasts were found to be deficient in gamma-ray ER of irradiated Ad2, and this defect appeared to be related to a marked relative radioresistance of unirradiated virus expression in AT compared to normal cells. The potential significance of these results is discussed in the context of mammalian ER, which is believed to be, at least in part, an expression of a mutagen-inducible (and possibly error-prone) DNA repair mechanism.
Carcinogenesis 1986 Mar
PMID:An aberration in gamma-ray-enhanced reactivation of irradiated adenovirus in ataxia telangiectasia fibroblasts. 394 23

Streptonigrin is an antitumour antibiotic, which at low doses produces DNA strand breaks in cultured cells leading, e.g., to decreased colony-forming ability and decreased rates of DNA synthesis. At higher doses the drug can induce unscheduled DNA synthesis (UDS) presumably as a consequence of excision of large DNA adducts. Ataxia telangiectasia (A-T) cells are unusually sensitive to streptonigrin, but we show here that they can perform excision repair, as demonstrated by UDS, at the same level as normal cells following exposure to the drug. This result suggests that of the apparent two modes of action of streptonigrin it is the DNA strand-breaking capacity to which A-T cells are unusually sensitive. This is consistent with previous reports suggesting some form of DNA strand break in A-T cells is deficiently repaired.
Carcinogenesis 1985 Jun
PMID:Unscheduled DNA synthesis induced by streptonigrin in ataxia telangiectasia fibroblasts. 400 84

Cells from patients with the hereditary multisystem disorder ataxia-telangiectasia (A-T) are hypersensitive to the cytotoxic action of DNA-breaking agents, such as X-rays, bleomycin and neocarzinostatin (NCS). A defect in the repair of a certain DNA lesion induced by all three agents may underlie this hypersensitivity. This DNA lesion may be a certain type of DNA strand break. Most of the previous experiments done with X-rays and bleomycin failed to show any retardation in the rejoining of DNA strand breaks in A-T cells. However, since both A-T homozygous and heterozygous cells are particularly hypersensitive to NCS, we studied the time course of strand breakage induction and repair in A-T skin fibroblast strains treated with NCS, using the sensitive method of alkaline or neutral elution. A linear dose response was obtained for the induction by NCS of single-strand breaks and double-strand breaks. A-T cells did not respond with a higher initial extent of strand breakage compared with normal cells. NCS is an appropriate agent for studying the kinetics of rejoining strand breaks, due to its rapid action in the cells; this action, which is completed within 2--4 min, was studied by monitoring strand break induction, inhibition of DNA synthesis and decrease in cellular survival. The time course of strand break rejoining found after NCS treatment was very similar to that found following X-irradiation: with both single- and double-strand breaks, a rapid phase of rejoining was first noticed (t 1/2 approximately 5 min for single-strand breaks and 20--25 min for double-strand breaks). This was followed by a second, slow phase that continued for several hours. No difference could be detected between normal and A-T cells either with regard to the time course of rejoining or the fraction of non-rejoined breaks remaining several hours after treatment.
Carcinogenesis 1983
PMID:Induction and repair of DNA damage in normal and ataxia-telangiectasia skin fibroblasts treated with neocarzinostatin. 622 17

The dysplastic nevus syndrome (DNS) is a preneoplastic melanocyte abnormality which occurs in families affected by hereditary cutaneous malignant melanoma (HCMM). A putative role of host-environmental interactions in the etiology of hereditary melanoma has been strengthened by the recent finding that fibroblasts derived from HCMM/DNS patients demonstrated enhanced sensitivity to u.v.-irradiation in vitro. We report here an extension of these studies in which we have examined the in vitro responses to a model environmental carcinogen, 4-nitroquinoline 1-oxide (4NQO), of six non-tumor skin fibroblast strains from HCMM/DNS patients representing five families. Three of the six HCMM/DNS strains showed enhanced cell killing with sensitivities greater than that of a xeroderma pigmentosum (XP) variant strain but less than those of ataxia telangiectasia and XP Group D cell strains. The inhibition and recovery of de novo DNA synthesis, together with the expression of repair synthesis, following 4NQO exposure appeared to be normal in HCMM/DNS strains, irrespective of their subsequent clonogenic potential. Our data point to a metabolic anomaly which may contribute to the carcinogenic risk of the melanoma prone preneoplastic state presented by some DNS patients.
Carcinogenesis 1983
PMID:Abnormal responses to the carcinogen 4-nitroquinoline 1-oxide of cultured fibroblasts from patients with dysplastic nevus syndrome and hereditary cutaneous malignant melanoma. 640 40

The cellular basis for the enhanced sensitivity to ionising radiation and some DNA damaging chemicals in ataxia-telangiectasia (AT) cells is not clearly understood. Abnormalities in cell-cycle traverse, chromosome stability and DNA synthesis patterns have suggested that a chromatin associated defect may be the primary lesion in AT. This study involves an attempt to define such an anomaly by the use of a vital DNA specific bis-benzimidazole dye (Hoechst 33342) and deoxyribonuclease II as probes for chromatin organisation in intact and permeabilised human cells respectively. Despite similar DNA binding characteristics (determined by flow cytometry) of Ho33342 in normal and AT transformed fibroblasts, the AT cells show: (i) enhanced cell killing and increased accumulation of cells in G2 phase of the cell-cycle [both biological responses being relatively resistant in AT cells to modification by an inhibitor of poly (ADP ribosyl)ation], (ii) no resistance of de novo DNA synthesis to Ho33342-induced inhibition, (iii) elevated levels of slow-rejoining ligand-induced DNA strand-breaks, and (iv) enhanced expression of chromatin regions accessible to an exogenously supplied endonuclease. The results are interpreted on the basis that a chromatin anomaly of enhanced nuclease susceptibility, involving a minor fraction of the genome, may be a controlling factor in the expression of the various in vivo and in vitro characteristics of AT cells.
Carcinogenesis 1984 Oct
PMID:Relationship between a chromatin anomaly in ataxia-telangiectasia cells and enhanced sensitivity to DNA damage. 648 55

A defect in DNA repair coupled to anomalous DNA synthesis after induction of certain radiogenic DNA damage is suspected to underlie the radiosensitivity of cells from patients with ataxia-telangiectasia (A-T). The response of cultured skin fibroblasts from A-T patients and A-T heterozygotes to six agents inducing various levels of DNA strand breakage by different mechanisms was studied to obtain further information on the nature of the 'A-T critical DNA lesion'. The A-T cells showed varying degrees of hypersensitivity to the cytotoxic action of the quinone-containing anti-tumor antibiotics streptonigrin and adriamycin and to hydrogen peroxide. This hypersensitivity was accompanied by reduced inhibition of DNA synthesis compared to normal cells after treatment with these agents. A limited degree of cellular hypersensitivity that was not sufficient to allow for definition of a separate sensitivity range was shown by A-T heterozygous cells. On the other hand, the A-T cells showed a normal response to paraquat, saframycin A and ellipticine. Taken together with previous results showing hypersensitivity of A-T cells to ionizing radiation, bleomycin and neocarzinostatin, these data indicate that the critical DNA lesion in A-T cells is a strand break caused by deoxyribose destruction following the action of free radicals targeted into the DNA.
Carcinogenesis 1983 Oct
PMID:Abnormal response of ataxia-telangiectasia cells to agents that break the deoxyribose moiety of DNA via a targeted free radical mechanism. 661 60


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