The DOI matches its Crossref record; 30 of the 30 references it cites were found in a registry or an index.
The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis
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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In the citing paper
“Both Chk1 and Chk2 regulate the functional associations between BRCA1, BRCA2, and Rad51 proteins in response to DNA damage, and thus promote HR-mediated repair of stalled replication forks [27, 28].”
From NER initiation factors, DDB2 and XPC, regulate UV radiation response by recruiting ATR and ATM kinases to DNA damage sites (2013) · cites this paper as [28]
In the citing paper
“Moreover, both the ATR-Chk1 and ATM-Chk2 pathways regulate HR-mediated repair of collapsed replication forks [27, 28].”
From NER initiation factors, DDB2 and XPC, regulate UV radiation response by recruiting ATR and ATM kinases to DNA damage sites (2013) · cites this paper as [28]
In the citing paper
“It has been established that spontaneous HR is promoted by collapsed replication forks that are caused by endogenous DNA SSB [24, 28].”
From NER initiation factors, DDB2 and XPC, regulate UV radiation response by recruiting ATR and ATM kinases to DNA damage sites (2013) · cites this paper as [28]
Citations
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Molecular Mechanisms of Mammalian DNA Repair and the DNA Damage Checkpoints
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Cell cycle checkpoint signaling through the ATM and ATR kinases
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Self-citation
Metadata
- Authors
- Falck, J., Mailand, N., Syljuåsen, R. G., Bartek, J., & Lukas, J.
- Affiliations
- Danish Cancer Society (DK)
- Venue
- Nature
- Published
- 2001-04
- Volume
- 410
- Issue
- 6830
- Pages
- 842-847
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- 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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