SCFβ-TRCP links Chk1 signaling to degradation of the Cdc25A protein phosphatase
Open accessAbstract
Eukaryotic cells respond to DNA damage and stalled replication forks by activating protein kinase-mediated signaling pathways that promote cell cycle arrest and DNA repair. A central target of the cell cycle arrest program is the Cdc25A protein phosphatase. Cdc25A is required for S-phase entry and dephosphorylates tyrosine-15 phosphorylated Cdk1 (Cdc2) and Cdk2, positive regulators of cell division. Cdc25A is unstable during S-phase and is degraded through the ubiquitin-proteasome pathway, but its turnover is enhanced in response to DNA damage. Although basal and DNA-damage-induced turnover depends on the ATM-Chk2 and ATR-Chk1 pathways, how these kinases engage the ubiquitin ligase machinery is unknown. Here, we demonstrate a requirement for SCF β-TRCP in Cdc25A turnover during an unperturbed cell cycle and in response to DNA damage. Depletion of β-TRCP stabilizes Cdc25A, leading to hyperactive Cdk2 activity. SCF β-TRCP promotes Chk1-dependent Cdc25A ubiquitination in vitro, and this involves serine 76, a known Chk1 phosphorylation site. However, recognition of Cdc25A by β-TRCP occurs via a noncanonical phosphodegron in Cdc25A containing phosphoserine 79 and phosphoserine 82, sites that are not targeted by Chk1. These data indicate that Cdc25A turnover is more complex than previously appreciated and suggest roles for an additional kinase(s) in Chk1-dependent Cdc25A turnover.
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A G2-phase DNA damage response causes claspin-dependent Chk1/2 activation and SCFβTrcP-mediated degradation of Cdc25A, arresting multiple cell-cycle transitions including the G2 checkpoint.
“The occurrence of DNA damage response in G2-phase, leads to checkpoint mediator (claspin) dependent activation of Chk1/2, followed by SCFβTrcP mediated degradation of CDK-activating phosphatase Cdc25A [341, 342], that results in arrest of multiple cell-cycle transition including the G2 checkpoint [343, 344].”
From Molecular Mechanisms of Ultraviolet Radiation‐Induced DNA Damage and Repair (2010) · cites this paper as [341]
The Abstract and Discussion (page not provided) support SCFβ-TRCP-mediated Cdc25A turnover in response to DNA damage and Chk1-dependent Cdc25A ubiquitination. They do not establish claspin-dependent Chk1/2 activation specifically in G2 phase. The sentence attaches separate citations to its later claim about arresting multiple cell-cycle transitions. (LLM, conf=0.86)
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- Authors
- Jin, J., Shirogane, T., Xu, L., Nalepa, G., Qin, J., Elledge, S. J., & Harper, J. W.
- Affiliations
- Howard Hughes Medical Institute (US)
- Baylor College of Medicine (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2003-01-01
- Volume
- 17
- Issue
- 24
- Pages
- 3062-3074
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC305258
- OpenAlex
- W2153708110
- Cited by
- 340
- References
- 59
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 2 · 2023: 6 · 2022: 5 · 2021: 12 · 2020: 13 · 2019: 6 · 2018: 9 · 2017: 11 · 2016: 14 · 2015: 16 · 2014: 18 · 2013: 17 · 2012: 25
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- U.S. Department of Defense
- Howard Hughes Medical Institute
- Sveriges Lantbruksuniversitet
- Japan Science Society
- National Institutes of Health
- National Institute on Aging (R01AG011085)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- CDC25A, ubiquitination, protein degradation, ubiquitin ligase, DNA damage response, ATR-Chk1 pathway, ATM-Chk2 pathway, phosphodegron, cell cycle arrest, S phase entry
- MeSH terms
- Checkpoint Kinase 1, Binding Sites, Cells, Cultured, DNA Damage, DNA Repair, Humans, Phosphorylation, Plasmids, Protein Binding, Protein Kinases, Radiation, Ionizing, Signal Transduction, S Phase, Cyclin E, cdc25 Phosphatases, Amino Acid Motifs, Ubiquitin, CDC2-CDC28 Kinases, SKP Cullin F-Box Protein Ligases, Cyclin-Dependent Kinase 2
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