Document Detail


Distinct mechanisms act in concert to mediate cell cycle arrest.
MedLine Citation:
PMID:  19139404     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Jared E Toettcher; Alexander Loewer; Gerard J Ostheimer; Michael B Yaffe; Bruce Tidor; Galit Lahav
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2009-01-12
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  106     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2009 Jan 
Date Detail:
Created Date:  2009-01-21     Completed Date:  2009-02-05     Revised Date:  2014-09-17    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  785-90     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Cell Cycle*
Cyclin-Dependent Kinase Inhibitor p21 / physiology
Cyclins / analysis
DNA Damage*
G1 Phase
G2 Phase
HCT116 Cells
Humans
Models, Biological
Tumor Suppressor Protein p53 / physiology
Grant Support
ID/Acronym/Agency:
GM083303/GM/NIGMS NIH HHS; P50 GM58762/GM/NIGMS NIH HHS; R01 GM065418/GM/NIGMS NIH HHS; R01 GM083303/GM/NIGMS NIH HHS; U54 CA112967/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/CDKN1A protein, human; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/Cyclins; 0/Tumor Suppressor Protein p53
Comments/Corrections

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