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A comprehensive model for the proliferation-quiescence decision in response to endogenous DNA damage in human cells
File | Description | Size | Format | |
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HeldtBarr_Pnas2018_Finalaccepted.pdf | Accepted version | 2.01 MB | Adobe PDF | View/Open |
Title: | A comprehensive model for the proliferation-quiescence decision in response to endogenous DNA damage in human cells |
Authors: | Heldt, FS Barr, AR Cooper, S Bakal, C Novak, B |
Item Type: | Journal Article |
Abstract: | Human cells that suffer mild DNA damage can enter a reversible state of growth arrest known as quiescence. This decision to temporarily exit the cell cycle is essential to prevent the propagation of mutations, and most cancer cells harbor defects in the underlying control system. Here we present a mechanistic mathematical model to study the proliferation–quiescence decision in nontransformed human cells. We show that two bistable switches, the restriction point (RP) and the G1/S transition, mediate this decision by integrating DNA damage and mitogen signals. In particular, our data suggest that the cyclin-dependent kinase inhibitor p21 (Cip1/Waf1), which is expressed in response to DNA damage, promotes quiescence by blocking positive feedback loops that facilitate G1 progression downstream of serum stimulation. Intriguingly, cells exploit bistability in the RP to convert graded p21 and mitogen signals into an all-or-nothing cell-cycle response. The same mechanism creates a window of opportunity where G1 cells that have passed the RP can revert to quiescence if exposed to DNA damage. We present experimental evidence that cells gradually lose this ability to revert to quiescence as they progress through G1 and that the onset of rapid p21 degradation at the G1/S transition prevents this response altogether, insulating S phase from mild, endogenous DNA damage. Thus, two bistable switches conspire in the early cell cycle to provide both sensitivity and robustness to external stimuli. |
Issue Date: | 6-Mar-2018 |
Date of Acceptance: | 29-Jan-2018 |
URI: | http://hdl.handle.net/10044/1/63449 |
DOI: | 10.1073/pnas.1715345115 |
ISSN: | 0027-8424 |
Publisher: | National Academy of Sciences |
Start Page: | 2532 |
End Page: | 2537 |
Journal / Book Title: | Proceedings of the National Academy of Sciences of the United States of America |
Volume: | 115 |
Issue: | 10 |
Copyright Statement: | © 2018 Published under the PNAS license (http://www.pnas.org/page/authors/licenses). |
Keywords: | Science & Technology Multidisciplinary Sciences Science & Technology - Other Topics cell cycle DNA damage proliferation-quiescence decision mathematical modelling live-cell imaging CYCLIN-DEPENDENT KINASES RESTRICTION POINT STOCHASTIC SIMULATION G(1) CONTROL S-PHASE P21 G1 CANCER PCNA REPLICATION Science & Technology Multidisciplinary Sciences Science & Technology - Other Topics cell cycle DNA damage proliferation-quiescence decision mathematical modelling live-cell imaging CYCLIN-DEPENDENT KINASES RESTRICTION POINT STOCHASTIC SIMULATION G(1) CONTROL S-PHASE P21 G1 CANCER PCNA REPLICATION DNA damage cell cycle live-cell imaging mathematical modelling proliferation–quiescence decision Cell Cycle Cell Proliferation Cells, Cultured Cyclin-Dependent Kinase Inhibitor p21 DNA Damage Gene Knockout Techniques Humans Mitogens Models, Biological Single-Cell Analysis Cells, Cultured Humans DNA Damage Mitogens Cell Cycle Cell Proliferation Models, Biological Cyclin-Dependent Kinase Inhibitor p21 Gene Knockout Techniques Single-Cell Analysis |
Publication Status: | Published |
Online Publication Date: | 2018-02-20 |
Appears in Collections: | Institute of Clinical Sciences Faculty of Medicine |