A Derivative of an Ataxia-telangiectasia (A-T) Cell Line with Normal Radiosensitivity but A-T-like Inhibition of DNA Synthesis

Lehmann, Alan R.; Arlett, C.F.; Burke, Julian F.; Green, M.H.L.; James, M. R.; Lowe, J.

doi:10.1080/09553008514552881

Cited by 49 publications

(13 citation statements)

References 15 publications

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“…Activation of the G2 checkpoint links mitosis to events occurring in S and possibly G1 phase and in this way might be expected to enhance survival after radiation exposure. In this context it is notable that enhanced radioresistance has been observed in transfected A-T cells without correction of the radioresistant DNA synthesis phenotype, indicating that a defect in the S phase checkpoint does not contribute to the radiosensitivity (Lehmann et al, 1986). On the contrary an enhancement of radioresistant DNA synthesis was observed when the yeast gene was expressed in A-T cells.…”

Section: Discussionmentioning

confidence: 96%

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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Section: Discussionmentioning

confidence: 96%

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

et al. 1999

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“…This phenotype, the so-called radioresistant DNA synthesis (RDS), is also a feature of ataxia telangiectasia (AT) cells, but the precise relation between RDS and radiation sensitivity is not clear. There are AT cell clones in which the cells no longer show RDS, but they remain radiation sensitive (Lehmann et al, 1986), thereby dissociating these two features of AT cells. BRCA1-deficient cells also show a defect in the G2/M phase cell cycle checkpoint (Xu et al, 1999b(Xu et al, , 2001, and this phenotype has long been associated with radiation sensitivity.…”

Section: Cell Cycle Checkpointsmentioning

confidence: 99%

Roles of BRCA1 and BRCA2 in homologous recombination, DNA replication fidelity and the cellular response to ionizing radiation

2003

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Inheritance of one defective copy of either of the two breast cancer susceptibility genes, BRCA1 and BRCA2, predisposes individuals to breast and ovarian cancers. Current progress in determining the function of these genes suggests that they participate in a common pathway to facilitate orderly homologous recombination and thereby maintain genomic integrity. As a consequence of this defect in homologous recombination, tumors that arise in BRCA carriers are likely to be more sensitive to ionizing radiation. This review summarizes recent investigations about the nature of the defect in DNA repair, and highlights the unanswered questions about the tumor suppressor paradox of BRCA genes. The unsolved mystery is the other genetic changes that must occur to turn a BRCA-deficient cell from a nonviable cell into a tumor cell capable of endless growth.

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“…Indeed, simply providing time for repair by manipulating growth conditions in protocols devised to evaluate repair of potentially lethal damage (PLD) (Iliakis, 1988) cannot modulate radiosensitivity in AT cells (Weichselbaum et al, 1978). Furthermore, genetic manipulations that restore checkpoint response in defective cell lines without correcting for radiosensitivity to killing have been described , and there is a report for an AT derivative cell line with wild-type radiosensitivity to killing that still displays RDS (Lehmann et al, 1986).…”

Section: Dna Damage Checkpoints and The Repair Of Dna Dsbsmentioning

confidence: 99%

DNA damage checkpoint control in cells exposed to ionizing radiation

et al. 2003

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Damage induced in the DNA after exposure of cells to ionizing radiation activates checkpoint pathways that inhibit progression of cells through the G1 and G2 phases and induce a transient delay in the progression through S phase. Checkpoints together with repair and apoptosis are integrated in a circuitry that determines the ultimate response of a cell to DNA damage. Checkpoint activation typically requires sensors and mediators of DNA damage, signal transducers and effectors. Here, we review the current state of knowledge regarding mechanisms of checkpoint activation and proteins involved in the different steps of the process. Emphasis is placed on the role of ATM and ATR, as well on CHK1 and CHK2 kinases in checkpoint response. The roles of downstream effectors, such as P53 and the CDC25 family of proteins, are also described, and connections between repair and checkpoint activation are attempted. The role of checkpoints in genomic stability and the potential of improving the treatment of cancer by DNA damage inducing agents through checkpoint abrogation are also briefly outlined.

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A Derivative of an Ataxia-telangiectasia (A-T) Cell Line with Normal Radiosensitivity but A-T-like Inhibition of DNA Synthesis

Cited by 49 publications

References 15 publications

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

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

Roles of BRCA1 and BRCA2 in homologous recombination, DNA replication fidelity and the cellular response to ionizing radiation

DNA damage checkpoint control in cells exposed to ionizing radiation

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