Is chromatid-type damage in ataxia telangiectasia after irradiation at G0 a consequence of defective repair?

Taylor, Alexander M.; Metcalfe, Judith A.; Oxford, J. M.; Harnden, D. G.

doi:10.1038/260441a0

Cited by 186 publications

(36 citation statements)

References 11 publications

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“…The results of these analysis showed that there is a slight but signi®cant reduction in these measurements in ATM 7/7 DT40 cell. These results therefore further support an idea that ATM plays some roles in HR DNA repair capacity, in addition to its established role in cell cycle checkpoint control (Taylor et al, 1976;Foray et al, 1997;Jeggo et al, 1998). However, it is dicult at the present time to exclude completely the phenotypic eects of the cell cycle defects, and the absence of p53 as well as ATM Values shown are the percentage of clones containing homologously integrated targeting construct relative to the total number of drugresistant clones analysed; absolute numbers are given in parentheses may make these ATM 7/7 DT40 cells a useful tool for further studying this element of ATM.…”

Section: Discussionsupporting

confidence: 73%

Disruption of ATM in p53-null cells causes multiple functional abnormalities in cellular response to ionizing radiation

et al. 1999

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ATM is a member of the large phosphatidylinositol-3 kinase family and plays an important role in cellular response to DNA damage. To further de®ne the physiological roles of ATM at the cellular level, we created an isogenic set of stable cell lines diering only in their ATM status from the chicken B cell line DT40 by targeted integration. These stable DT40 cell lines, as most of transformed chicken cell lines, do not express p53. However, ATM 7/7 DT40 cells displayed retarded cellular proliferation, defective G 2 /M checkpoint control and radio-resistant DNA synthesis. Furthermore, ATM 7/7 DT40 cells were sensitive to ionizing radiation and showed highly elevated frequencies of both spontaneous and radiation-induced chromosomal aberrations. In addition, a slight but signi®cant reduction in targeted integration frequency was observed in ATM 7/7 DT40 cells. These results suggest that ATM has multiple p53-independent functions in cell cycle checkpoint control and in maintenance of chromosomal DNA. These ATM de®cient DT40 clones therefore provide a useful model system for analysing p53-independent ATM functions.

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Section: Discussionsupporting

confidence: 73%

Disruption of ATM in p53-null cells causes multiple functional abnormalities in cellular response to ionizing radiation

et al. 1999

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“…Inactivation of p53 ablates G1 checkpoint function and is associated with gene ampli®cation and chromosomal instability in human ®broblasts (Yin et al, 1992;Livingstone et al, 1992;White et al, 1994). Ataxia telangiectasia cells that are defective in both G1 and G2 checkpoint functions display enhanced frequencies of spontaneous and radiation-induced chromosomal aberrations (Taylor et al, 1976;Zampetti-Bosseler and Scott, 1981;Ejima and Sasaki, 1986). Defects in G2 checkpoint function were associated with enhanced frequencies of radiationinduced chromosome breaks in a panel of human cancer lines (Schwartz et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Chromosomal instability is correlated with telomere erosion and inactivation of G2 checkpoint function in human fibroblasts expressing human papillomavirus type 16 E6 oncoprotein

et al. 1998

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Cell cycle checkpoints and tumor suppressor gene functions appear to be required for the maintenance of a stable genome in proliferating cells. In this study chromosomal destabilization was monitored in relation to telomere structure, lifespan control and G2 checkpoint function. Replicative senescence was inactivated in secondary cultures of human skin ®broblasts by expressing the human papillomavirus type 16 (HPV-16) E6 oncoprotein to inactivate p53. Chromosome aberrations were enumerated during in vitro aging of isogenic control (F5neo) and HPV-16E6-expressing (F5E6) ®broblasts. We found that structural and numerical aberrations in chromosomes were signi®cantly increased in F5E6 cells during aging in vitro and¯uorescence in situ hybridization (FISH) analysis using chromosome-speci®c probes demonstrated the occurrence of rearrangements involving chromosome 4 and 6 in genetically unstable F5E6 cells. Flow cytometry and karyotypic analyses revealed increased polyploidy and aneuploidy in F5E6 cells only at passages 416, although these cells displayed defective mitotic spindle checkpoint function associated with inactivation of p53 at passages 5 and 16. G2 checkpoint function was con®rmed to be gradually but progressively inactivated during in vitro aging of E6-expressing cells. Aging of F5neo ®broblasts was documented during in vitro passaging by induction of a senescence-associated marker, pH 6.0 lysosomal b-galactosidase. F5E6 cells displayed extension of in vitro lifespan and did not induce b-galactosidase at high passage. Erosion of telomeres during in vitro aging of telomerase-negative F5neo cells was demonstrated by Southern hybridization and by quantitative FISH analysis on an individual cell level. Telomeric signals diminished continuously as F5neo cells aged in vitro being reduced by 80% near the time of replicative senescence. Telomeric signals detected by FISH also decreased continuously during aging of telomerasenegative F5E6 cells, but telomeres appeared to be stabilized at passage 34 when telomerase was expressed. Chromosomal instability in E6-expressing cells was correlated (P50.05) with both loss of telomeric signals and inactivation of G2 checkpoint function. The results suggest that chromosomal stability depends upon a complex interaction among the systems of telomere length maintenance and cell cycle checkpoints.

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“…For both wild-type and ATM À/À cells, SCE numbers were less than two per cell. It is well established that ionizing radiation exposure leads to an increase in chromosomal aberrations in A-T cells (Taylor et al, 1976;Chen et al, 1978). More recently, the intermediate levels of radiation-induced DNA damage have been reported for BS lymphoblastoid cells (Beamish et al, 2002).…”

Section: Chromosomal Instability In Atmmentioning

confidence: 99%

Disruption of the BLM gene in ATM-null DT40 cells does not exacerbate either phenotype

et al. 2004

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Bloom syndrome and ataxia-telangiectasia are autosomal recessive human disorders characterized by immunodeficiency, genome instability and predisposition to develop cancer. Recent data reveal that the products of these two genes, BLM and ATM, interact and function together in recognizing abnormal DNA structures. To investigate the function of these two molecules in DNA damage recognition, we generated double knockouts of ATM cells. There was no evidence for exacerbation of either phenotype; however, the more extreme radiosensitivity seen in ATM À/À and the elevated sister chromatid exchange seen in BLM À/À cells were retained in the double mutants. These results suggest that ATM and BLM have largely distinct roles in recognizing different forms of damage in DNA, but are also compatible with partially overlapping functions in recognizing breaks in radiation-damaged DNA.

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Is chromatid-type damage in ataxia telangiectasia after irradiation at G0 a consequence of defective repair?

Cited by 186 publications

References 11 publications

Disruption of ATM in p53-null cells causes multiple functional abnormalities in cellular response to ionizing radiation

Disruption of ATM in p53-null cells causes multiple functional abnormalities in cellular response to ionizing radiation

Chromosomal instability is correlated with telomere erosion and inactivation of G2 checkpoint function in human fibroblasts expressing human papillomavirus type 16 E6 oncoprotein

Disruption of the BLM gene in ATM-null DT40 cells does not exacerbate either phenotype

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