The DOI matches its Crossref record; 33 of the 33 references it cites were found in a registry or an index.
The cell-cycle checkpoint kinase Chk1 is required for mammalian homologous recombination repair
Abstract
The essential checkpoint kinase Chk1 is required for cell-cycle delays after DNA damage or blocked DNA replication. However, it is unclear whether Chk1 is involved in the repair of damaged DNA. Here we establish that Chk1 is a key regulator of genome maintenance by the homologous recombination repair (HRR) system. Abrogation of Chk1 function with small interfering RNA or chemical antagonists inhibits HRR, leading to persistent unrepaired DNA double-strand breaks (DSBs) and cell death after replication inhibition with hydroxyurea or DNA-damage caused by camptothecin. After hydroxyurea treatment, the essential recombination repair protein RAD51 is recruited to DNA repair foci performing a vital role in correct HRR. We demonstrate that Chk1 interacts with RAD51, and that RAD51 is phosphorylated on Thr 309 in a Chk1-dependent manner. Consistent with a functional interplay between Chk1 and RAD51, Chk1-depleted cells failed to form RAD51 nuclear foci after exposure to hydroxyurea, and cells expressing a phosphorylation-deficient mutant RAD51(T309A) were hypersensitive to hydroxyurea. These results highlight a crucial role for the Chk1 signalling pathway in protecting cells against lethal DNA lesions through regulation of HRR.
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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 [27]
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 [27]
In the citing paper
“activated Chk1 phosphorylates its own substrates such as protein Rad51, which is involved in the DSB repair by HR [193–195]”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [195]
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Metadata
- Authors
- Sørensen, C. S., Hansen, L. T., Dziegielewski, J., Syljuåsen, R. G., Lundin, C., Bartek, J., & Helleday, T.
- Affiliations
- Danish Cancer Society (DK)
- University of Copenhagen (DK)
- University of Sheffield (GB)
- Stockholm University (SE)
- Corresponding author
- Helleday, Thomas
- Venue
- Nature Cell Biology
- Published
- 2005-01-23
- Volume
- 7
- Issue
- 2
- Pages
- 195-201
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- OpenAlex
- W2149795092
- Cited by
- 666
- References
- 33
- Citations by year
- 2026: 12 · 2025: 13 · 2024: 18 · 2023: 38 · 2022: 26 · 2021: 38 · 2020: 41 · 2019: 23 · 2018: 31 · 2017: 31 · 2016: 37 · 2015: 44 · 2014: 37 · 2013: 35 · 2012: 48
- FWCI
- 11.55
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Keywords
- Chk1, homologous recombination repair, RAD51, DNA double-strand break repair, DNA damage response, cell cycle checkpoints, hydroxyurea, camptothecin, genome maintenance, replication inhibition
- MeSH terms
- Checkpoint Kinase 1, Animals, Camptothecin, DNA, DNA Damage, DNA Repair, DNA-Binding Proteins, Cricetinae, Humans, Hydroxyurea, Protein Kinases, Recombination, Genetic, Signal Transduction, Rad51 Recombinase
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