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The intra-S phase checkpoint affects both DNA replication initiation and elongation: single-cell and -DNA fiber analyses
Open accessAbstract
To investigate the contribution of DNA replication initiation and elongation to the intra-S-phase checkpoint, we examined cells treated with the specific topoisomerase I inhibitor camptothecin. Camptothecin is a potent anticancer agent producing well-characterized replication-mediated DNA double-strand breaks through the collision of replication forks with topoisomerase I cleavage complexes. After a short dose of camptothecin in human colon carcinoma HT29 cells, DNA replication was inhibited rapidly and did not recover for several hours following drug removal. That inhibition occurred preferentially in late-S-phase, compared to early-S-phase, cells and was due to both an inhibition of initiation and elongation, as determined by pulse-labeling nucleotide incorporation in replication foci and DNA fibers. DNA replication was actively inhibited by checkpoint activation since 7-hydroxystaurosporine (UCN-01), the specific Chk1 inhibitor CHIR-124, or transfection with small interfering RNA targeting Chk1 restored both initiation and elongation. Abrogation of the checkpoint markedly enhanced camptothecin-induced DNA damage at replication sites where histone gamma-H2AX colocalized with replication foci. Together, our study demonstrates that the intra-S-phase checkpoint is exerted by Chk1 not only upon replication initiation but also upon DNA elongation.
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“However, in response to camptothecin, inhibition of CHK1 accelerates both the speed of replication fork elongation and origin firing [35, 36].”
From The Spi1/PU.1 transcription factor accelerates replication fork progression by increasing PP1 phosphatase in leukemia (2017) · cites this paper as [35]
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Metadata
- Authors
- Seiler, J. A., Conti, C., Syed, A., Aladjem, M. I., & Pommier, Y.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Pommier, Yves
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2007-08-01
- Volume
- 27
- Issue
- 16
- Pages
- 5806-5818
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC1952133
- OpenAlex
- W2171439401
- Cited by
- 226
- References
- 71
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 6 · 2023: 11 · 2022: 6 · 2021: 14 · 2020: 7 · 2019: 8 · 2018: 15 · 2017: 16 · 2016: 22 · 2015: 17 · 2014: 11 · 2013: 12 · 2012: 13
- FWCI
- 6.10
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer therapeutics and mechanisms
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- S-phase checkpoint, DNA replication initiation, DNA replication elongation, Chk1, camptothecin, topoisomerase I cleavage complexes, DNA damage response, γH2AX, replication foci, single-cell analysis, CHK1 inhibition, HT-29 cells
- MeSH terms
- Camptothecin, DNA, DNA Damage, DNA Replication, Histones, Humans, Models, Biological, S Phase, Replication Origin, HT29 Cells, Staurosporine, Protein Transport
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