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A comprehensive model for the proliferation-quiescence decision in response to endogenous DNA damage in human cells

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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: https://dx.doi.org/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
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
MD Multidisciplinary
Publication Status: Published
Online Publication Date: 2018-02-20
Appears in Collections:Clinical Sciences
Molecular Sciences



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