Chk1 promotes replication fork progression by controlling replication initiation
Open accessAbstract
DNA replication starts at initiation sites termed replication origins. Metazoan cells contain many more potential origins than are activated (fired) during each S phase. Origin activation is controlled by the ATR checkpoint kinase and its downstream effector kinase Chk1, which suppresses origin firing in response to replication blocks and during normal S phase by inhibiting the cyclin-dependent kinase Cdk2. In addition to increased origin activation, cells deficient in Chk1 activity display reduced rates of replication fork progression. Here we investigate the causal relationship between increased origin firing and reduced replication fork progression. We use the Cdk inhibitor roscovitine or RNAi depletion of Cdc7 to inhibit origin firing in Chk1-inhibited or RNAi-depleted cells. We report that Cdk inhibition and depletion of Cdc7 can alleviate the slow replication fork speeds in Chk1-deficient cells. Our data suggest that increased replication initiation leads to slow replication fork progression and that Chk1 promotes replication fork progression during normal S phase by controlling replication origin activity.
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CHK1 inhibition slows replication fork progression associated with an increased origin firing in mammals.
“It has been reported that CHK1 inhibition slows replication fork progression associated with an increased origin firing in mammals [16, 17].”
From The Spi1/PU.1 transcription factor accelerates replication fork progression by increasing PP1 phosphatase in leukemia (2017) · cites this paper as [16]
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References 40 · Cited by 308
- Authors
- Petermann, E., Woodcock, M., & Helleday, T.
- Affiliations
- University of Oxford (GB)
- Stockholm University (SE)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2010-08-30
- Volume
- 107
- Issue
- 37
- Pages
- 16090-16095
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2941317
- OpenAlex
- W2082861064
- Cited by
- 308
- References
- 40
- Citations by year
- 2026: 10 · 2025: 11 · 2024: 15 · 2023: 21 · 2022: 11 · 2021: 36 · 2020: 24 · 2019: 12 · 2018: 28 · 2017: 21 · 2016: 27 · 2015: 19 · 2014: 17 · 2013: 27 · 2012: 15
- FWCI
- 7.42
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Funders
- Cancer Research UK
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- Chk1, replication fork progression, replication initiation, origin firing, CDK2, CDC7, roscovitine, S phase, DNA replication
- MeSH terms
- Checkpoint Kinase 1, DNA, DNA Replication, Humans, Protein Kinases, S Phase, Protein Serine-Threonine Kinases, Cell Cycle Proteins, RNA Interference, Cell Line, Tumor
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