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A double-strand break repair defect in ATM-deficient cells contributes to radiosensitivity

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A double-strand break repair defect in ATM-deficient cells contributes to radiosensitivity. / Kühne, Martin; Riballo, Enriqueta; Rief, Nicole; Rothkamm, Kai; Jeggo, Penny A; Löbrich, Markus.

In: CANCER RES, Vol. 64, No. 2, 15.01.2004, p. 500-8.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Kühne, M, Riballo, E, Rief, N, Rothkamm, K, Jeggo, PA & Löbrich, M 2004, 'A double-strand break repair defect in ATM-deficient cells contributes to radiosensitivity', CANCER RES, vol. 64, no. 2, pp. 500-8. https://doi.org/10.1158/0008-5472.can-03-2384

APA

Kühne, M., Riballo, E., Rief, N., Rothkamm, K., Jeggo, P. A., & Löbrich, M. (2004). A double-strand break repair defect in ATM-deficient cells contributes to radiosensitivity. CANCER RES, 64(2), 500-8. https://doi.org/10.1158/0008-5472.can-03-2384

Vancouver

Kühne M, Riballo E, Rief N, Rothkamm K, Jeggo PA, Löbrich M. A double-strand break repair defect in ATM-deficient cells contributes to radiosensitivity. CANCER RES. 2004 Jan 15;64(2):500-8. https://doi.org/10.1158/0008-5472.can-03-2384

Bibtex

@article{9bd9f231d690477d80778d6d8e0ae309,
title = "A double-strand break repair defect in ATM-deficient cells contributes to radiosensitivity",
abstract = "The ATM protein, which is mutated in individuals with ataxia telangiectasia (AT), is central to cell cycle checkpoint responses initiated by DNA double-strand breaks (DSBs). ATM's role in DSB repair is currently unclear as is the basis underlying the radiosensitivity of AT cells. We applied immunofluorescence detection of gamma-H2AX nuclear foci and pulsed-field gel electrophoresis to quantify the repair of DSBs after X-ray doses between 0.02 and 80 Gy in confluence-arrested primary human fibroblasts from normal individuals and patients with mutations in ATM and DNA ligase IV, a core component of the nonhomologous end-joining (NHEJ) repair pathway. Cells with hypomorphic mutations in DNA ligase IV exhibit a substantial repair defect up to 24 h after treatment but continue to repair for several days and finally reach a level of unrepaired DSBs similar to that of wild-type cells. Additionally, the repair defect in NHEJ mutants is dose dependent. ATM-deficient cells, in contrast, repair the majority of DSBs with normal kinetics but fail to repair a subset of breaks, irrespective of the initial number of lesions induced. Significantly, after biologically relevant radiation doses and/or long repair times, the repair defect in AT cells is more pronounced than that of NHEJ mutants and correlates with radiosensitivity. NHEJ-defective cells analyzed for survival following delayed plating after irradiation show substantial recovery while AT cells fail to show any recovery. These data argue that the DSB repair defect underlies a significant component of the radiosensitivity of AT cells.",
keywords = "Ataxia Telangiectasia, Ataxia Telangiectasia Mutated Proteins, Cell Cycle Proteins, Cell Line, DNA Damage, DNA Ligase ATP, DNA Ligases/genetics, DNA Repair/genetics, DNA-Binding Proteins, Dose-Response Relationship, Radiation, Electrophoresis, Gel, Pulsed-Field, Fibroblasts/physiology, Humans, Immunoblotting, Kinetics, Lung/cytology, Protein-Serine-Threonine Kinases/deficiency, Radiation Tolerance, Tumor Suppressor Proteins, X-Rays",
author = "Martin K{\"u}hne and Enriqueta Riballo and Nicole Rief and Kai Rothkamm and Jeggo, {Penny A} and Markus L{\"o}brich",
year = "2004",
month = jan,
day = "15",
doi = "10.1158/0008-5472.can-03-2384",
language = "English",
volume = "64",
pages = "500--8",
journal = "CANCER RES",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "2",

}

RIS

TY - JOUR

T1 - A double-strand break repair defect in ATM-deficient cells contributes to radiosensitivity

AU - Kühne, Martin

AU - Riballo, Enriqueta

AU - Rief, Nicole

AU - Rothkamm, Kai

AU - Jeggo, Penny A

AU - Löbrich, Markus

PY - 2004/1/15

Y1 - 2004/1/15

N2 - The ATM protein, which is mutated in individuals with ataxia telangiectasia (AT), is central to cell cycle checkpoint responses initiated by DNA double-strand breaks (DSBs). ATM's role in DSB repair is currently unclear as is the basis underlying the radiosensitivity of AT cells. We applied immunofluorescence detection of gamma-H2AX nuclear foci and pulsed-field gel electrophoresis to quantify the repair of DSBs after X-ray doses between 0.02 and 80 Gy in confluence-arrested primary human fibroblasts from normal individuals and patients with mutations in ATM and DNA ligase IV, a core component of the nonhomologous end-joining (NHEJ) repair pathway. Cells with hypomorphic mutations in DNA ligase IV exhibit a substantial repair defect up to 24 h after treatment but continue to repair for several days and finally reach a level of unrepaired DSBs similar to that of wild-type cells. Additionally, the repair defect in NHEJ mutants is dose dependent. ATM-deficient cells, in contrast, repair the majority of DSBs with normal kinetics but fail to repair a subset of breaks, irrespective of the initial number of lesions induced. Significantly, after biologically relevant radiation doses and/or long repair times, the repair defect in AT cells is more pronounced than that of NHEJ mutants and correlates with radiosensitivity. NHEJ-defective cells analyzed for survival following delayed plating after irradiation show substantial recovery while AT cells fail to show any recovery. These data argue that the DSB repair defect underlies a significant component of the radiosensitivity of AT cells.

AB - The ATM protein, which is mutated in individuals with ataxia telangiectasia (AT), is central to cell cycle checkpoint responses initiated by DNA double-strand breaks (DSBs). ATM's role in DSB repair is currently unclear as is the basis underlying the radiosensitivity of AT cells. We applied immunofluorescence detection of gamma-H2AX nuclear foci and pulsed-field gel electrophoresis to quantify the repair of DSBs after X-ray doses between 0.02 and 80 Gy in confluence-arrested primary human fibroblasts from normal individuals and patients with mutations in ATM and DNA ligase IV, a core component of the nonhomologous end-joining (NHEJ) repair pathway. Cells with hypomorphic mutations in DNA ligase IV exhibit a substantial repair defect up to 24 h after treatment but continue to repair for several days and finally reach a level of unrepaired DSBs similar to that of wild-type cells. Additionally, the repair defect in NHEJ mutants is dose dependent. ATM-deficient cells, in contrast, repair the majority of DSBs with normal kinetics but fail to repair a subset of breaks, irrespective of the initial number of lesions induced. Significantly, after biologically relevant radiation doses and/or long repair times, the repair defect in AT cells is more pronounced than that of NHEJ mutants and correlates with radiosensitivity. NHEJ-defective cells analyzed for survival following delayed plating after irradiation show substantial recovery while AT cells fail to show any recovery. These data argue that the DSB repair defect underlies a significant component of the radiosensitivity of AT cells.

KW - Ataxia Telangiectasia

KW - Ataxia Telangiectasia Mutated Proteins

KW - Cell Cycle Proteins

KW - Cell Line

KW - DNA Damage

KW - DNA Ligase ATP

KW - DNA Ligases/genetics

KW - DNA Repair/genetics

KW - DNA-Binding Proteins

KW - Dose-Response Relationship, Radiation

KW - Electrophoresis, Gel, Pulsed-Field

KW - Fibroblasts/physiology

KW - Humans

KW - Immunoblotting

KW - Kinetics

KW - Lung/cytology

KW - Protein-Serine-Threonine Kinases/deficiency

KW - Radiation Tolerance

KW - Tumor Suppressor Proteins

KW - X-Rays

U2 - 10.1158/0008-5472.can-03-2384

DO - 10.1158/0008-5472.can-03-2384

M3 - SCORING: Journal article

C2 - 14744762

VL - 64

SP - 500

EP - 508

JO - CANCER RES

JF - CANCER RES

SN - 0008-5472

IS - 2

ER -