Cited by 1,085DNA Repair MechanismsCancer-related Molecular PathwaysEffects of Radiation Exposure

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The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis

Falck, Jacob, Mailand, Niels, Syljuåsen, Randi G., Bartek, Jiri, Lukas, Jiri·2001·Nature

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Abstract

When exposed to ionizing radiation (IR), eukaryotic cells activate checkpoint pathways to delay the progression of the cell cycle. Defects in the IR-induced S-phase checkpoint cause 'radioresistant DNA synthesis', a phenomenon that has been identified in cancer-prone patients suffering from ataxia-telangiectasia, a disease caused by mutations in the ATM gene. The Cdc25A phosphatase activates the cyclin-dependent kinase 2 (Cdk2) needed for DNA synthesis, but becomes degraded in response to DNA damage or stalled replication. Here we report a functional link between ATM, the checkpoint signalling kinase Chk2/Cds1 (Chk2) and Cdc25A, and implicate this mechanism in controlling the S-phase checkpoint. We show that IR-induced destruction of Cdc25A requires both ATM and the Chk2-mediated phosphorylation of Cdc25A on serine 123. An IR-induced loss of Cdc25A protein prevents dephosphorylation of Cdk2 and leads to a transient blockade of DNA replication. We also show that tumour-associated Chk2 alleles cannot bind or phosphorylate Cdc25A, and that cells expressing these Chk2 alleles, elevated Cdc25A or a Cdk2 mutant unable to undergo inhibitory phosphorylation (Cdk2AF) fail to inhibit DNA synthesis when irradiated. These results support Chk2 as a candidate tumour suppressor, and identify the ATM-Chk2-Cdc25A-Cdk2 pathway as a genomic integrity checkpoint that prevents radioresistant DNA synthesis.

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Authors: Falck, J., Mailand, N., Syljuåsen, R. G., Bartek, J., & Lukas, J.
Affiliations: Danish Cancer Society (DK)
ORCID: Mailand, Niels
Syljuåsen, Randi G.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2001-04
Volume: 410
Issue: 6830
Pages: 842-847
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/35071124
OpenAlex: W1480741751
Cited by: 1,085
References: 30
Citations by year: 2026: 14 · 2025: 11 · 2024: 22 · 2023: 20 · 2022: 24 · 2021: 29 · 2020: 19 · 2019: 31 · 2018: 24 · 2017: 30 · 2016: 40 · 2015: 30 · 2014: 37 · 2013: 43 · 2012: 55
FWCI: 29.91
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Funders: National Institute on Aging
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
Keywords: radioresistant DNA synthesis, ATM, Chk2, CDC25A, CDK2, S-phase checkpoint, ionizing radiation, DNA damage response, tumour suppressor, ataxia telangiectasia, DNA replication inhibition, protein phosphorylation
MeSH terms: Alleles, Animals, Cell Cycle, Cell Line, DNA Replication, DNA-Binding Proteins, Humans, Phosphorylation, Protein Kinases, Radiation Tolerance, Radiation, Ionizing, Serine, Transfection, Signal Transduction, S Phase, Protein Serine-Threonine Kinases, Cell Cycle Proteins, cdc25 Phosphatases, Tumor Suppressor Proteins, Mice, Ataxia Telangiectasia Mutated Proteins, Checkpoint Kinase 2

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The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis

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