Induction and Rejoining of Chromatid Breaks in X-irradiated A-T and Normal Human G<sub>2</sub>Fibroblasts

Mozdarani, Hossein; Bryant, Peter E.

doi:10.1080/09553008914551861

Cited by 8 publications

(5 citation statements)

References 16 publications

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“…results with the comet assay indicate that the elevated chromosomal damage observed in treated AT cells is not due to a difference in the initial level of SS or DS DNA damage or in the rate of rejoining of strand breaks. Previous reports on the repair capacity of AT cells using X-irradition as the DNAdamaging agent suggest that the AT defect is not in SS DNA breakage and rejoining [Fornace and Little, 1980;Hariharan etal., 1981;Fornaceetal., 1986;Cantonietal., 19891, orin the initial level of DS DNA breakage [Coquerelle and Weibezahn, 1981;Coquerelle et al, 1987;Radford and Hodgson, 1990;Hittelman, 1992a, 1992bl. However, there may be a difference in the way AT cells process DS DNA damage [Coquerelle and Weibezahn, 1981;Coquerelle et al, 1987;George and Cramp, 1987;Debenham et al, 1987;Mozdarani and Bryant, 1989;Radford and Hodgson, 1990;Blocher et al, 1991;Hittelman, 1992a, 1992bl. Our results indicate no difference in rejoining rate, or extent of rejoining. Since heavily damaged cells can be excluded from analysis, rejoining rates using the comet assay may be a more accurate indicator of repair.…”

Section: Acknowledgmentsmentioning

confidence: 99%

Response of fibroblast cultures from ataxia‐telangiectasia patients to reactive oxygen species generated during inflammatory reactions

Ward

Olive²,

Burr

et al. 1994

Environ and Mol Mutagen

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Cells from patients with ataxia-telangiectasia (AT) are more sensitive than cells from normal individuals to a number of compounds which induce DNA damage via oxygen-derived free radical attack. We tested the hypothesis that AT cells would show a sensitivity to reactive oxygen species (ROS) generated by activated inflammatory cells. AT cells were exposed to neutrophils activated with 12-O-tetradecanoyl-phorbol-13-acetate (TPA) or to xanthine/xanthine oxidase (X/XO), an enzyme system which generates superoxide and hydrogen peroxide. Induced micronuclei (MN) frequencies (corrected for spontaneous MN frequencies) were significantly higher in AT cell cultures than in cultures from normal individuals (comparison of MN frequencies of AT vs. normal cultures: for treatment with activated neutrophils, P = 0.003; for X/XO, P = 0.05). The comet assay was used to determine whether the elevated chromosomal damage in the treated AT cells was due to a difference in strand breakage or its rejoining. X/XO treatment was used in studies of single-stranded (SS) DNA breakage, and X-ray treatment for double-stranded (DS) DNA damage. AT and normal cells showed no significant differences in the initial levels of SS (P = 0.29) or DS (P = 0.91) DNA damage. Likewise, they exhibited similar rejoining kinetics (rejoining half-time for SS = 10 min, for DS = 30 min). These data support the involvement of the AT loci in determining a cell's ability to deal with oxidative stress, although the mechanism underlying this effect has yet to be resolved. The data also suggest that AT patients are at elevated risk of sustaining DNA damage in tissues undergoing inflammatory reactions.

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Section: Acknowledgmentsmentioning

confidence: 99%

Response of fibroblast cultures from ataxia‐telangiectasia patients to reactive oxygen species generated during inflammatory reactions

Ward

Olive²,

Burr

et al. 1994

Environ and Mol Mutagen

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“…over the period of the "G 2 assay" of chromatid breaks) although much higher frequencies of chromatid breaks are observed in (AT) G 2 than in normal control irradiated cells (Taylor, 1978;Mozdarani and Bryant, 1989;Antoccia et al, 1994). Similarly, we find that the mutant hamster cell line irs2 (assigned to the mammalian XRCC8 gene, the function of which is not yet known; Thacker and Zdzienicka, 2003) shows an elevated frequency of "G 2 " chromatid breaks (242 breaks per 100 cells) compared to its parental V79 line (143 breaks per 100 cells) but no defect in DSB induction or rejoining is observed after 30 Gy (Fig.…”

Section: Interchromatid Typesmentioning

confidence: 99%

Progress towards understanding the nature of chromatid breakage

Bryant¹,

Gray²,

Peresse³

2004

Cytogenet Genome Res

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The wide range of sensitivities of stimulated T-cells from different individuals to radiation-induced chromatid breakage indicates the involvement of several low penetrance genes that appear to link elevated chromatid breakage to cancer susceptibility. The mechanisms of chromatid breakage are not yet fully understood. However, evidence is accumulating that suggests chromatid breaks are not simply expanded DNA double-strand breaks (DSB). Three models of chromatid breakage are considered. The classical breakage-first and the Revell “exchange” models do not accord with current evidence. Therefore a derivative of Revell’s model has been proposed whereby both spontaneous and radiation-induced chromatid breaks result from DSB signaling and rearrangement processes from within large looped chromatin domains. Examples of such rearrangements can be observed by harlequin staining whereby an exchange of strands occurs immediately adjacent to the break site. However, these interchromatid rearrangements comprise less than 20% of the total breaks. The rest are thought to result from intrachromatid rearrangements, including a very small proportion involving complete excision of a looped domain. Work is in progress with the aim of revealing these rearrangements, which may involve the formation of inversions adjacent to the break sites. It is postulated that the disappearance of chromatid breaks with time results from the completion of such rearrangements, rather than from the rejoining of DSB. Elevated frequencies of chromatid breaks occur in irradiated cells with defects in both nonhomologous end-joining (NHEJ) and homologous recombination (HR) pathways, however there is little evidence of a correlation between reduced DSB rejoining and disappearance of chromatid breaks. Moreover, at least one treatment which abrogates the disappearance of chromatid breaks with time leaves DSB rejoining unaffected. The I-SceI DSB system holds considerable promise for the elucidation of these mechanisms, although the break frequency is relatively low in the cell lines so far derived. Techniques to study and improve such systems are under way in different cell lines. Clearly, much remains to be done to clarify the mechanisms involved in chromatid breakage, but the experimental models are becoming available with which we can begin to answer some of the key questions.

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“…Radiation-induced instability endpoints have been shown to be manifested as chromosomal alterations, micronuclei, cell transformation, gene amplification, apoptosis, and sister chromatid exchange, etc . The induction of the unstable CA following the exposure of cells at the G1 phase and chromatid-type aberrations after the irradiation of cells at the G2 phase of the cell cycle, is quite characteristic of ionizing radiation [20,21,22,23]. The studies on derived mutants of mammalian cells which are deficient in the repair of DSBs show a high chromosomal sensitivity [24,25,26] and also, the generation of DSB in the DNA of the cells by the restriction endonucleases [27,28] strongly argues in favor of the DSB as the lesion, leading to CA in the irradiated cells.…”

Section: Radiation Carcinogenesismentioning

confidence: 99%

“…These chromosome breakage syndromes are characterized by various defects in DNA repair, predisposition to various forms of malignancies and increased radiosensitivity [23,45,50,51,52]. The chromosome breakage syndromes such as ataxia-telangiectasia , Nijmegen breakage syndrome, ataxia-telangiectasia -like disorder, Bloom syndrome, Werner syndrome and Fanconi anemia are human autosomal recessive diseases characterized by inherited chromosomal instability and cancer predisposition [48,53,54].…”

Section: Impact Of Radiosensitivity On Carcinogenesis and Cancer Tmentioning

confidence: 99%

“…These enhanced chromatid aberrations have been attributed to repair deficiency in DNA of these cells [81], that it has genetic basis and also is associated with genetic susceptibility to cancer [68]. High frequency of chromatid type aberrations were detected in radiosenistive cell lines such as AT, SCID and Irs2 defective in DNA damage repair [23,26,82]. …”

Section: Impact Of Radiosensitivity On Carcinogenesis and Cancer Tmentioning

confidence: 99%

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Biological Complexities in Radiation Carcinogenesis and Cancer Radiotherapy: Impact of New Biological Paradigms

Mozdarani

2012

Genes

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Although radiation carcinogenesis has been shown both experimentally and epidemiologically, the use of ionizing radiation is also one of the major modalities in cancer treatment. Various known cellular and molecular events are involved in carcinogenesis. Apart from the known phenomena, there could be implications for carcinogenesis and cancer prevention due to other biological processes such as the bystander effect, the abscopal effect, intrinsic radiosensitivity and radioadaptation. Bystander effects have consequences for mutation initiated cancer paradigms of radiation carcinogenesis, which provide the mechanistic justification for low-dose risk estimates. The abscopal effect is potentially important for tumor control and is mediated through cytokines and/or the immune system (mainly cell-mediated immunity). It results from loss of growth and stimulatory and/or immunosuppressive factors from the tumor. Intrinsic radiosensitivity is a feature of some cancer prone chromosomal breakage syndromes such as ataxia telangectiasia. Radiosensitivity is manifested as higher chromosomal aberrations and DNA repair impairment is now known as a good biomarker for breast cancer screening and prediction of prognosis. However, it is not yet known whether this effect is good or bad for those receiving radiation or radiomimetic agents for treatment. Radiation hormesis is another major concern for carcinogenesis. This process which protects cells from higher doses of radiation or radio mimic chemicals, may lead to the escape of cells from mitotic death or apoptosis and put cells with a lower amount of damage into the process of cancer induction. Therefore, any of these biological phenomena could have impact on another process giving rise to genome instability of cells which are not in the field of radiation but still receiving a lower amount of radiation. For prevention of radiation induced carcinogenesis or risk assessment as well as for successful radiation therapy, all these phenomena should be taken into account.

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Induction and Rejoining of Chromatid Breaks in X-irradiated A-T and Normal Human G₂Fibroblasts

Cited by 8 publications

References 16 publications

Response of fibroblast cultures from ataxia‐telangiectasia patients to reactive oxygen species generated during inflammatory reactions

Response of fibroblast cultures from ataxia‐telangiectasia patients to reactive oxygen species generated during inflammatory reactions

Progress towards understanding the nature of chromatid breakage

Biological Complexities in Radiation Carcinogenesis and Cancer Radiotherapy: Impact of New Biological Paradigms

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Induction and Rejoining of Chromatid Breaks in X-irradiated A-T and Normal Human G2Fibroblasts

Cited by 8 publications

References 16 publications

Response of fibroblast cultures from ataxia‐telangiectasia patients to reactive oxygen species generated during inflammatory reactions

Response of fibroblast cultures from ataxia‐telangiectasia patients to reactive oxygen species generated during inflammatory reactions

Progress towards understanding the nature of chromatid breakage

Biological Complexities in Radiation Carcinogenesis and Cancer Radiotherapy: Impact of New Biological Paradigms

Contact Info

Product

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Induction and Rejoining of Chromatid Breaks in X-irradiated A-T and Normal Human G₂Fibroblasts