Cited by 666DNA Repair MechanismsPARP inhibition in cancer therapyFungal and yeast genetics research

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The cell-cycle checkpoint kinase Chk1 is required for mammalian homologous recombination repair

Sørensen, Claus Storgaard, Hansen, Lasse Tengbjerg, Dziegielewski, Jaroslaw, Syljuåsen, Randi G., Lundin, Cecilia, Bartek, Jiri, Helleday, Thomas·2005·Nature Cell Biology

DOI 10.1038/ncb1212

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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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Dibitetto, D., Sims, J. R., Ascenção, C. F. R., Feng, K., Freire, R., & Smolka, M. B. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.01.13.905059
Replication stress: mechanisms and molecules involved in dna replication progression and reinitiation
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RECQL4; Linking DNA Replication and Bone Tumourigenesis
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Role of 5-FU in DNA double strand break repair for improved targets in colorectal cancer therapy
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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
ORCID: Sørensen, Claus Storgaard
Syljuåsen, Randi G.
Lundin, Cecilia
Helleday, Thomas
Venue: Nature Cell Biology
Publisher: Springer Science and Business Media LLC
Published: 2005-01-23
Volume: 7
Issue: 2
Pages: 195-201
ISSN: 1465-7392 (ISSN-L)
1476-4679
DOI: 10.1038/ncb1212
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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The cell-cycle checkpoint kinase Chk1 is required for mammalian homologous recombination repair

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