Distinct mechanisms act in concert to mediate cell cycle arrest
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In response to DNA damage, cells arrest at specific stages in the cell cycle. This arrest must fulfill at least 3 requirements: it must be activated promptly; it must be sustained as long as damage is present to prevent loss of genomic information; and after the arrest, cells must re-enter into the appropriate cell cycle phase to ensure proper ploidy. Multiple molecular mechanisms capable of arresting the cell cycle have been identified in mammalian cells; however, it is unknown whether each mechanism meets all 3 requirements or whether they act together to confer specific functions to the arrest. To address this question, we integrated mathematical models describing the cell cycle and the DNA damage signaling networks and tested the contributions of each mechanism to cell cycle arrest and re-entry. Predictions from this model were then tested with quantitative experiments to identify the combined action of arrest mechanisms in irradiated cells. We find that different arrest mechanisms serve indispensable roles in the proper cellular response to DNA damage over time: p53-independent cyclin inactivation confers immediate arrest, whereas p53-dependent cyclin downregulation allows this arrest to be sustained. Additionally, p21-mediated inhibition of cyclin-dependent kinase activity is indispensable for preventing improper cell cycle re-entry and endoreduplication. This work shows that in a complex signaling network, seemingly redundant mechanisms, acting in a concerted fashion, can achieve a specific cellular outcome.
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A model proposes that cells stably blocked in G2 undergo mitotic bypass into tetraploid G1, where p21-mediated inhibition of cyclin E1-Cdk2 prevents replication.
“A model originally proposed by the Lahav group suggests that cells stably blocked in G2 eventually undergo mitotic bypass -a passage from G2 to G1 without chromosome segregation -and enter a tetraploid G1 phase where they cannot replicate due to p21-mediated inhibition of cyclin E1-Cdk2.89”
From Senescence from G2 arrest, revisited (2015) · cites this paper as [89]
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- Authors
- Toettcher, J. E., Loewer, A., Ostheimer, G. J., Yaffe, M. B., Tidor, B., & Lahav, G.
- Affiliations
- Harvard University (US)
- Center for Cancer Research (US)
- Massachusetts Institute of Technology (US)
- Corresponding author
- Toettcher, Jared E.
- Loewer, Alexander
- Lahav, Galit
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-01-20
- Volume
- 106
- Issue
- 3
- Pages
- 785-790
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2630102
- OpenAlex
- W2041969498
- Cited by
- 112
- References
- 40
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 7 · 2023: 3 · 2022: 7 · 2021: 7 · 2020: 5 · 2019: 10 · 2018: 7 · 2017: 4 · 2016: 3 · 2015: 6 · 2014: 7 · 2013: 9 · 2012: 6
- FWCI
- 5.83
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (CA112967)
- National Cancer Institute (U54CA112967)
- National Institute of General Medical Sciences (R01GM083303, GM083303, R01GM058762, R01GM065418, P50 GM58762)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Physical Sciences › Mathematics › Modeling and Simulation › Mathematical Biology Tumor Growth
- Keywords
- cell cycle arrest, DNA damage response, p21, cyclin-dependent kinase inhibition, cell cycle re-entry, endoreduplication, ionizing radiation, genome stability
- MeSH terms
- Cell Cycle, DNA Damage, Humans, Models, Biological, Tumor Suppressor Protein p53, G1 Phase, G2 Phase, Cyclins, HCT116 Cells, Cyclin-Dependent Kinase Inhibitor p21
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