Cited by 112Cancer-related Molecular PathwaysDNA Repair MechanismsMathematical Biology Tumor Growth

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Distinct mechanisms act in concert to mediate cell cycle arrest

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Toettcher, Jared E., Loewer, Alexander, Ostheimer, Gerard J., Yaffe, Michael B., Tidor, Bruce, Lahav, Galit·2009·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.0806196106PMC PMC2630102

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Abstract

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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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: Toettcher, Jared E.
Loewer, Alexander
Ostheimer, Gerard J.
Yaffe, Michael B.
Tidor, Bruce
Lahav, Galit
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
DOI: 10.1073/pnas.0806196106
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
Licence: www.pnas.org/site/misc/userlicense.xhtml (vor, 181 d)
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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Distinct mechanisms act in concert to mediate cell cycle arrest

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