Identification of ataxia telangiectasia heterozygotes, a cancer prone population

Chen, Philip G.; Lavin, Martin F.; Kidson, Chev; Moss, Denis J.

doi:10.1038/274484a0

Cited by 204 publications

(77 citation statements)

References 11 publications

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“…Many authors have reported a level of cell survival intermediate between that seen in normal and ATM homozygote cells, but, in other studies, some overlap or no statistically significant differences between normal and AT het cell types have been detected (Chen et al, 1978;Kinsella et al, 1982;Nagasawa et al, 1985;Weeks et al, 1991;West et al, 1995;Shigeta et al, 1999;Sun et al, 2002). Many of these studies have used a fibroblast-cloning assay, which requires the trypsinising and replating of treated cells, which may lead to additional cell death, particularly in radiationsensitive cell types.…”

Section: Discussionmentioning

confidence: 90%

“…For instance, intermediate sensitivity to IR has been documented in cell lines from AT heterozygotes using the measurement of cell survival or chromosome damage induction as end points (Chen et al, 1978;Rosin and Ochs, 1986;Shiloh et al, 1986;Scott et al, 1996;Tchirkov et al, 1997;Neubauer et al, 2002). However, many such studies have characterised only cell lines carrying truncating mutations, and some variability in the cellular responses has been noted between different cell lines (Nagasawa et al, 1985;Shiloh et al, 1989;Pandita and Hittelman, 1994;Djuzenova et al, 1999).…”

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confidence: 99%

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Cellular responses to ionising radiation of AT heterozygotes: differences between missense and truncating mutation carriers

et al. 2004

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It has been estimated that approximately 1% of the general population are ataxia telangiectasia (AT) mutated (ATM) heterozygotes. The ATM protein plays a central role in DNA-damage response pathways; however, the functional consequences of the presence of either heterozygous truncating or missense mutations on ATM expression and the ionising radiation (IR)-induced cellular phenotype remain to be fully determined. To investigate this relationship, the ATM mRNA and protein levels and several cellular end points were characterised in 14 AT heterozygote (AT het) lymphoblastoid cell lines, compared to normal and AT homozygote lines. The AT het cell lines displayed a wide range of IR-induced responses: despite lower average levels of ATM mRNA and protein expression compared to normal cells, 13 out of 14 were capable of phosphorylating the ATM substrates p53-ser15 and Chk2, leading to a normal cell cycle progression after irradiation. However, cell survival was lower than in the normal cell lines. The presence of a missense compared to a truncating mutation was associated with lower cell survival after exposure to 2 Gy irradiation (P ¼ 0.005), and a higher level of ATM mRNA expression (P ¼ 0.047). Our results underline the difficulty in establishing a reliable test for determining ATM heterozygosity.

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Section: Discussionmentioning

confidence: 90%

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confidence: 99%

Cellular responses to ionising radiation of AT heterozygotes: differences between missense and truncating mutation carriers

et al. 2004

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“…Hypersensitivity to ionizing radiation is observed in A-T patients exposed to therapeutic radiation (Goto et al, 1967;Morgan et al, 1968) and in cultured cells from these patients (Taylor et al, 1975;Chen et al, 1978). There is evidence that this radiosensitivity is due to passage of damaged cells through the cell cycle and to the eventual accumulation of these cells in G2/M where they die (Beamish and Lavin, 1994).…”

Section: Chk1 Increases Radioresistance In A-t Cells As Determined Bymentioning

confidence: 99%

Chk1 complements the G2/M checkpoint defect and radiosensitivity of ataxia-telangiectasia cells

et al. 1999

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Cells from patients with the human genetic disorder ataxia-telangiectasia (A-T) are defective in the activation of cell cycle checkpoints in response to ionizing radiation damage. In order to understand the role of ATM in checkpoint control we investigated whether Schizosaccaromyces pombe chk1, a protein kinase implicated in controlling the G2 DNA damage checkpoint, might alter the radiosensitive phenotype in A-T cells. The ®ssion yeast chk1 gene was cloned into an EBV-based vector under the control of a metallothionein promoter and transfected into A-T lymphoblastoid cells. Induction of chk1 enhanced the survival of an A-T cell line in response to radiation exposure as determined by cell viability and reduction of radiation-induced chromosome aberrations. This can be accounted for at least in part by the restoration of the G2 checkpoint to chk1 expressing cells. There was no evidence that chk1 expression corrected either the G1/S checkpoint or radioresistant DNA synthesis in S phase in these cells. These results suggest that chk1 when overexpressed acts downstream from ATM to restore the G2 checkpoint in these cells and correct the radiosensitive phenotype. These data allow us to dissociate individual checkpoint events and relate them to the radiosensitive phenotype in A-T cells.

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“…It is well established that cells with the mutated form of ATM are hypersensitive to ionizing radiation (Taylor et al, 1975;Chen et al, 1978). Accordingly, we investigated whether elimination of the ATM protein in control cells might lead to a radiosensitive phenotype.…”

Section: Increased Radiosensitivity In C3abr Cells After Atm Anti-senmentioning

confidence: 99%

“…At the cellular level A-T is characterized by chromosomal instability (Aurias et al, 1980), hypersensitivity to ionizing radiation (Chen et al, 1978;Taylor et al, 1975) and ine cient cell cycle checkpoint activation (Beamish and Lavin, 1994;Zampetti-Bossler and Scott, 1981). The exact cause of the radiosensitivity in A-T cells remains unknown but there is evidence that the rejoining of g-radiation-induced double strand breaks is slower in A-T ®broblasts (Coquerelle et al, 1987).…”

Section: Introductionmentioning

confidence: 99%

An anti-sense construct of full-length ATM cDNA imposes a radiosensitive phenotype on normal cells

et al. 1998

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Identification of ataxia telangiectasia heterozygotes, a cancer prone population

Cited by 204 publications

References 11 publications

Cellular responses to ionising radiation of AT heterozygotes: differences between missense and truncating mutation carriers

Cellular responses to ionising radiation of AT heterozygotes: differences between missense and truncating mutation carriers

Chk1 complements the G2/M checkpoint defect and radiosensitivity of ataxia-telangiectasia cells

An anti-sense construct of full-length ATM cDNA imposes a radiosensitive phenotype on normal cells

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