Distinct mechanisms act in concert to mediate cell cycle arrest.

TitleDistinct mechanisms act in concert to mediate cell cycle arrest.
Publication TypeJournal Article
Year of Publication2009
AuthorsToettcher, JE, Loewer, A, Ostheimer, GJ, Yaffe, MB, Tidor, B, Lahav, G
JournalProc Natl Acad Sci U S A
Date Published2009 Jan 20
KeywordsCell Cycle, Cyclin-Dependent Kinase Inhibitor p21, Cyclins, DNA Damage, G1 Phase, G2 Phase, HCT116 Cells, Humans, Models, Biological, Tumor Suppressor Protein p53

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.

Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID19139404
PubMed Central IDPMC2630102
Grant ListGM083303 / GM / NIGMS NIH HHS / United States
P50 GM58762 / GM / NIGMS NIH HHS / United States
R01 GM065418-07 / GM / NIGMS NIH HHS / United States
R01 GM083303-03 / GM / NIGMS NIH HHS / United States
U54 CA112967 / CA / NCI NIH HHS / United States