Rejoining of DNA double‐strand breaks in human fibroblasts and its impairment in one ataxia telangiectasia and two fanconi strains

Coquerelle, Thérèse; Weibezahn, Karl-Friedrich

doi:10.1002/jsscb.380170408

Cited by 45 publications

(8 citation statements)

References 16 publications

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“…In addition, alterations of the FA protein complex can also affect chromatin transformation during replication and DNA damage repair. The slow kinetics of the restitution of DNA damage in irradiated FA cells shown here by the Comet assay ( Figure 2) is in line with the defects of the DNA repair mechanism earlier reported for FA cells [13,42]. As shown recently, the repair of DNA DSBs by homologous recombination in FA cells is altered [14,18,52].…”

Section: Discussionsupporting

confidence: 72%

Radiation Response in Vitro of Fibroblasts from a Fanconi Anemia Patient with Marked Clinical Radiosensitivity

2004

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. The increased DNA damage and MN induction in irradiated FA fibroblasts, and the reduction of the formation of DNA repair foci containing Rad51 suggest a possible link to the profound clinical radiosensitivity reported earlier for this FA patient. The findings on this particular FA cell strain presented in the study point toward the difficulties involved in the prediction of the radiation response of cell lines and tumors based solely on the colony survival test.

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Section: Discussionsupporting

confidence: 72%

Radiation Response in Vitro of Fibroblasts from a Fanconi Anemia Patient with Marked Clinical Radiosensitivity

2004

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“…Additionally, cells from another cancer-prone genetic disorder, ataxia telangiectasia, as well as FA cells were shown previously to develop chromatid breaks or gaps after xirradiation during G2 (3,8,9). The higher incidence of chromatid breaks in these previous studies probably resulted from the longer irradiation-fixation interval, [3][4][5][6] study. During this longer interval, gaps could be converted into breaks (11).…”

Section: Discussionmentioning

confidence: 99%

“…A deficiency in the repair of UV-induced DNA damage was described in 1968 (1) in cells from XP individuals with a high incidence of skin cancer. Subsequently, studies on ataxia telangiectasia and FA cells provided some evidence that these cells may be defective in repair of DNA damage produced by ionizing radiation or DNA crosslinking agents (2)(3)(4)(5)(6)(7)(8)(9). However, numerous attempts with biochemical methods have failed to reveal a DNA repair deficiency(ies) in all of these genetic disorders.…”

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confidence: 99%

Chromatid damage after G2 phase x-irradiation of cells from cancer-prone individuals implicates deficiency in DNA repair.

Parshad¹,

Sanford²,

Jones³

1983

Proc. Natl. Acad. Sci. U.S.A.

109

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Ten lines. of. skin fibroblasts from individuals with genetic disorders predisposing to a high risk of cancer were compared with nine lines from normal adult-donors with respect to chromatid damage after x-irradiation [25, 50, and 100 rad (0.25 0.50, and 1 gray)] during G2 phase. The 10 cell lines represented five genetic disorders: Bloom syndrome, familial polyposis, Fanconi anemia, Gardner syndrome, and xeroderma.pigmentosum, complementation groups A(XP-A), C(XP-C), E(XP-E), and variant (XP-Va).. The incidence of chromatid breaks in all cancer-prone lines except XP-E and XP-A was significantly higher. than in the normal lines; The incidence of chromatid gaps in all cancer-prone lines except XP-A and XP-Va was significantly higher than in the normal lines. Because each chromatid apparently contains a-single continuous DNA double strand, chromatid breaks and gaps represent unrepaired DNA strand breaks arising directly or indirectly during excision repair of x-ray-inducedDNA damage. These cytogenetic data together with results-from use of the DNA repair.inhibitor arabinofuranosyl cytosine (cytosine arabinoside) suggest that cells from all of these cancer-prone individuals are deficient in some step of DNA repair, predominantly excision repair operative during the G2-prophase period of the cell cycle.-It appears that these DNA repair. deficiencies are associated with a genetic predisposition to a high risk of cancer.A number of inherited human disorders, including ataxia telangiectasia, Gardner syndrome (GS), familial polyposis (FP), Fanconi anemia (FA), Bloom syndrome (BS), and xeroderma pigmentosum (XP), predispose the individual to a high risk of cancer. Cells from these individuals are useful for elucidating mechanisms of carcinogenesis. A deficiency in the repair of UV-induced DNA damage was described in 1968 (1) in cells from XP individuals with a high incidence of skin cancer. Subsequently, studies on ataxia telangiectasia and FA cells provided some evidence that these cells may be defective in repair of DNA damage produced by ionizing radiation or DNA crosslinking agents (2-9). However, numerous attempts with biochemical methods have failed to reveal a DNA repair deficiency(ies) in all of these genetic disorders. When exposed to ionizing radiation during the G2 phase of the cell cycle, skin fibroblasts from ataxia telangiectasia and FA individuals show a high incidence of chromatid breaks or gaps at metaphase compared.with cells from normal individuals (3,8,9). Because. each chromatid apparently contains a single continuous DNA double strand, chromatid breaks and gaps represent unrepaired DNA strand breaks (3,[8][9][10][11][12][13][14][15][16][17]. These strand breaks could arise directly or indirectly during excision repair of the DNA damage produced by ionizing radiation (9, 13, 16). In view of this interpretation of cytogenetic results, cells from at least two of the.genetic disorders, ataxia telangiectasia and FA, appear to have a DNA repair defect operative during G2-prophase.The present stud...

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“…Thus, the existence of a highly damaged subpopulation helps to explain seemingly contradictory notions of normal repair, 4-9 but increased DNA break numbers soon after irradiation. [10][11][12][13] However, another reason for discordant observations with respect to DNA repair in AT might be the use of cycling versus non-cycling AT cells in diVerent reports. Our study was carried out to determine whether the cell cycle influences the numbers of DNA breaks detected in irradiated AT cells.…”

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confidence: 99%

Cell cycle dependent DNA break increase in ataxia telangiectasia lymphoblasts after radiation exposure

Humar¹

2001

Molecular Pathology

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The most striking feature of ataxia telangiectasia (AT) cells is their profound sensitivity to ionising radiation. A deficiency in the rejoining of radiation induced DNA breaks has been suggested to be responsible for AT radiosensitivity; however, the existing literature is controversial. A subpopulation, which is present in irradiated AT lymphoblasts, but rarely in controls, has been reported previously. The cells that make up this subpopulation harbour highly fragmented DNA and are responsible for the overall increase in DNA breaks soon after irradiation in AT lymphoblasts. This study examines the influence of the cell cycle on the highly damaged subpopulation. The frequency of highly damaged cells was highest when AT lymphoblasts were irradiated during the G2/M phase. In contrast, AT lymphoblasts irradiated during the G0/G1 phase displayed a frequency similar to control cells. Thus, only G2/M and to some extent S phase cells contribute to an increased DNA break number in AT lymphoblasts early after irradiation. These findings might explain several inconsistencies reported in the literature. (J Clin Pathol: Mol Pathol 2001;54:347-350)

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Rejoining of DNA double‐strand breaks in human fibroblasts and its impairment in one ataxia telangiectasia and two fanconi strains

Cited by 45 publications

References 16 publications

Radiation Response in Vitro of Fibroblasts from a Fanconi Anemia Patient with Marked Clinical Radiosensitivity

Radiation Response in Vitro of Fibroblasts from a Fanconi Anemia Patient with Marked Clinical Radiosensitivity

Chromatid damage after G2 phase x-irradiation of cells from cancer-prone individuals implicates deficiency in DNA repair.

Cell cycle dependent DNA break increase in ataxia telangiectasia lymphoblasts after radiation exposure

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