Adaptation of a DNA Replication Checkpoint Response Depends upon Inactivation of Claspin by the Polo-like Kinase
Open accessAbstract
The checkpoint mediator protein Claspin is essential for the ATR-dependent activation of Chk1 in Xenopus egg extracts containing aphidicolin-induced DNA replication blocks. We show that, during this checkpoint response, Claspin becomes phosphorylated on threonine 906 (T906), which creates a docking site for Plx1, the Xenopus Polo-like kinase. This interaction promotes the phosphorylation of Claspin on a nearby serine (S934) by Plx1. After a prolonged interphase arrest, aphidicolin-treated egg extracts typically undergo adaptation and enter into mitosis despite the presence of incompletely replicated DNA. In this process, Claspin dissociates from chromatin, and Chk1 undergoes inactivation. By contrast, aphidicolin-treated extracts containing mutants of Claspin with alanine substitutions at positions 906 or 934 (T906A or S934A) are unable to undergo adaptation. Under such adaptation-defective conditions, Claspin accumulates on chromatin at high levels, and Chk1 does not decrease in activity. These results indicate that the Plx1-dependent inactivation of Claspin results in termination of a DNA replication checkpoint response.
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After DNA damage is repaired or a pathway is selected, the ATR-Chk1 checkpoint is terminated by adaptation or recovery to resume normal cell cycle progression, which may require Plk1-mediated phosphorylation and degradation of Claspin.
“After DNA damage is repaired or a pathway selection has been made, the ATR-Chk1 checkpoint will be terminated using checkpoint adaption or a recovery mechanism to resume normal cell cycle progression, which may require Plk1-mediated phosphorylation and subsequent degradation of Claspin [134, 135].”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [135]
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References 36 · Cited by 228
- Authors
- Yoo, H. Y., Kumagai, A., Shevchenko, A., Shevchenko, A., & Dunphy, W. G.
- Affiliations
- California Institute of Technology (US)
- Max Planck Institute of Molecular Cell Biology and Genetics (DE)
- Corresponding author
- Dunphy, William G.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2004-05
- Volume
- 117
- Issue
- 5
- Pages
- 575-588
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2131761459
- Cited by
- 228
- References
- 36
- Citations by year
- 2025: 4 · 2024: 1 · 2023: 8 · 2022: 7 · 2021: 7 · 2020: 6 · 2019: 10 · 2018: 2 · 2017: 8 · 2016: 7 · 2015: 8 · 2014: 16 · 2013: 12 · 2012: 14
- FWCI
- 6.99
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (GM-43974)
- 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
- Claspin, Polo-like kinase, DNA replication checkpoint, checkpoint adaptation, ATR signaling, chromatin association, mitosis entry, Xenopus egg extracts, aphidicolin
- MeSH terms
- Polo-Like Kinase 1, Animals, Carrier Proteins, Cell Cycle, Chromatin, DNA Replication, Enzyme Inhibitors, Ovum, Phosphorylation, Xenopus, Aphidicolin, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Xenopus Proteins, Adaptor Proteins, Signal Transducing, Ataxia Telangiectasia Mutated Proteins
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