The Cdc14B-Cdh1-Plk1 Axis Controls the G2 DNA-Damage-Response Checkpoint
Open accessAbstract
In response to DNA damage in G2, mammalian cells must avoid entry into mitosis and instead initiate DNA repair. Here, we show that, in response to genotoxic stress in G2, the phosphatase Cdc14B translocates from the nucleolus to the nucleoplasm and induces the activation of the ubiquitin ligase APC/C(Cdh1), with the consequent degradation of Plk1, a prominent mitotic kinase. This process induces the stabilization of Claspin, an activator of the DNA-damage checkpoint, and Wee1, an inhibitor of cell-cycle progression, and allows an efficient G2 checkpoint. As a by-product of APC/C(Cdh1) reactivation in DNA-damaged G2 cells, Claspin, which we show to be an APC/C(Cdh1) substrate in G1, is targeted for degradation. However, this process is counteracted by the deubiquitylating enzyme Usp28 to permit Claspin-mediated activation of Chk1 in response to DNA damage. These findings define a novel pathway that is crucial for the G2 DNA-damage-response checkpoint.
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Premature p21-dependent APC/C-Cdh1 activation in G2-arrested cells was thought to result from Emi1 downregulation, although a Cdc14B role was not formally excluded.
“This premature and p21-dependent activation of APC/C-Cdh1 in G2arrested cells was thought to be due to down-regulation of the APC/C inhibitor Emi1, 74 although an implication of the Cdc14B phosphatase in this process was not formally excluded.77”
From Senescence from G2 arrest, revisited (2015) · cites this paper as [77]
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Retracted
- Authors
- Bassermann, F., Frescas, D., Guardavaccaro, D., Busino, L., Peschiaroli, A., & Pagano, M.
- Affiliations
- New York University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Pagano, Michele
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2008-07
- Volume
- 134
- Issue
- 2
- Pages
- 256-267
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC2591934
- OpenAlex
- W1963937857
- Cited by
- 397
- References
- 52
- Citations by year
- 2026: 8 · 2025: 4 · 2024: 9 · 2023: 19 · 2022: 12 · 2021: 21 · 2020: 26 · 2019: 15 · 2018: 24 · 2017: 19 · 2016: 26 · 2015: 18 · 2014: 25 · 2013: 21 · 2012: 38
- FWCI
- 15.21
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1878 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Cancer Institute (R21CA125173, R37CA076584)
- National Institute of General Medical Sciences (R01GM057587)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- CDC14B, CDH1, PLK1, G2 checkpoint, DNA damage response, anaphase-promoting complex, Claspin, WEE1, Chk1, USP28, deubiquitination, protein degradation, genotoxic stress
- MeSH terms
- Polo-Like Kinase 1, Cell Nucleus, DNA Damage, DNA Repair, Humans, Mitosis, Neoplasms, Proto-Oncogene Proteins, Signal Transduction, G2 Phase, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Ubiquitin Thiolesterase, Ubiquitin-Protein Ligase Complexes, Cell Line, Tumor, Adaptor Proteins, Signal Transducing, Dual-Specificity Phosphatases, Anaphase-Promoting Complex-Cyclosome
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