A Double-Strand Break Repair Defect in ATM-Deficient Cells Contributes to Radiosensitivity
Open accessAbstract
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 γ-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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In ATM/ATR-deficient cells, the radiosensitive phenotype has been attributed to double-strand break repair defects.
“Moreover, in ATM/ATR-deficient cells, the radiosensitive phenotype has been ascribed to the double-strand break repair defects (26,27).”
From Phosphorylation of Nucleotide Excision Repair Factor Xeroderma Pigmentosum Group A by Ataxia Telangiectasia Mutated and Rad3-Related–Dependent Checkpoint Pathway Promotes Cell Survival in Response to UV Irradiation (2006) · cites this paper as [26]
The Abstract and Discussion attribute a significant component of radiosensitivity in ATM-deficient cells to failure to repair a subset of double-strand breaks. The paper studies ATM deficiency, not ATR deficiency, so it does not support the ATR part of the citing sentence. (LLM, conf=0.90)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 64 · Cited by 347
- Authors
- Kühne, M., Riballo, E., Rief, N., Rothkamm, K., Jeggo, P. A., & Löbrich, M.
- Affiliations
- 1Fachrichtung Biophysik, Universität des Saarlandes, Homburg/Saar, Germany, and
- University of Sussex (GB)
- Saarland University (DE)
- Venue
- Cancer Research
- Published
- 2004-01-15
- Volume
- 64
- Issue
- 2
- Pages
- 500-508
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2012759709
- Cited by
- 347
- References
- 64
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 7 · 2023: 9 · 2022: 4 · 2021: 9 · 2020: 10 · 2019: 15 · 2018: 10 · 2017: 8 · 2016: 8 · 2015: 20 · 2014: 18 · 2013: 21 · 2012: 16
- FWCI
- 10.18
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Figshare (submittedVersion, cc-by)
- Sussex Research Online (University of Sussex) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Keywords
- ATM, ataxia telangiectasia, DNA double-strand break repair, radiosensitivity, DNA ligase IV, non-homologous end joining, γH2AX foci, X-ray irradiation, cell cycle checkpoints, repair kinetics, hypomorphic mutation
- MeSH terms
- DNA Ligase ATP, Ataxia Telangiectasia, Cell Line, DNA Damage, DNA Repair, DNA-Binding Proteins, Dose-Response Relationship, Radiation, Fibroblasts, Humans, Kinetics, Lung, DNA Ligases, Radiation Tolerance, X-Rays, Immunoblotting, Electrophoresis, Gel, Pulsed-Field, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Tumor Suppressor Proteins, Ataxia Telangiectasia Mutated Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
