The DOI matches its Crossref record; 39 of the 40 references it cites were found in a registry or an index.
Distinct mechanisms act in concert to mediate cell cycle arrest
Open accessAbstract
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 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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Requirement for p53 and p21 to Sustain G 2 Arrest After DNA Damage
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Inhibition of cyclin-dependent kinases by p21.
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Cell Cycle Arrest After DNA Damage
Toettcher, J. E. (2013) · Springer eBooks · doi:10.1007/978-1-4419-9863-7_47 · Cited by 3
Self-citationSerum deprivation enhanced ethanol-induced toxic responses in A549, lung carcinoma cells
Khare, P., Singh, V. K., & Bala, L. (2022) · Journal of Environmental Biology · doi:10.22438/jeb/43/1/mrn-1860 · Cited by 2
Characterization and function of the nek11 kinase in cancer cells
Sabir, S. R. (2015) · Figshare · Cited by 2
Buzby, J. S., Williams, S. A., & Nugent, D. J. (2022) · Genes · doi:10.3390/genes13122302 · Cited by 1
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Molecules, cells and minds : aspects of bioscientific explanation
Powell, A. M. (2009) · UPT. Syiah Kuala University Library (Syiah Kuala University) · Cited by 1
Biphasic JNK–Erk Signaling Separates Induction and Maintenance of Cell Senescence after DNA DamagePreprint
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Self-citationMahjoub, S., Dhiflaoui, A., Almawi, W. Y., Mahjoub, T., Morjani, H., Martiny, L., Devarenne-Charpentier, E., & Btaouri, H. E. (2022) · Research Square · doi:10.21203/rs.3.rs-2216622/v1
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Abuchery, B. E., Teixeira, T. L., da Silva, V. L., Marques, R. B., Gerolamo, F. M., Shukla, A. K., Catta‐Preta, C. M. C., Santarossa, B. A., Lapsley, C. T., Ferri, Y. G., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.01.21.700787
Structure, Dynamics, and Evolution of the Intrinsically Disordered p53 Transactivation Domain
Borcherds, W. M. (2013) · Digital Commons - University of South Florida (University of South Florida)
Development of novel therapies for colorectal carcinoma using dietary indoles
Brookes, A. (2014) · Leicester Research Archive (University of Leicester)
Metadata
- 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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