Heldt2018 - Proliferation-quiescence decision in response to DNA damage

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Model Identifier
BIOMD0000000700
Short description
Heldt2018 - Proliferation-quiescence decision in response to DNA damage

This model is described in the article:

Heldt FS, Barr AR, Cooper S, Bakal C, Novák B.
Proc. Natl. Acad. Sci. U.S.A. 2018 Feb; :

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.

This model is hosted on BioModels Database and identified by: MODEL1703030000.

To cite BioModels Database, please use: Chelliah V et al. BioModels: ten-year anniversary. Nucl. Acids Res. 2015, 43(Database issue):D542-8.

To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Format
SBML (L2V4)
Related Publication
  • A comprehensive model for the proliferation-quiescence decision in response to endogenous DNA damage in human cells.
  • Frank Stefan Heldt, Barr AR, Cooper S, Bakal C, Novák B
  • Proceedings of the National Academy of Sciences of the United States of America , 3/ 2018 , Volume 115 , Issue 10 , pages: 2532-2537 , PubMed ID: 29463760
  • Department of Biochemistry, University of Oxford, OX1 3QU Oxford, United Kingdom; stefan.heldt@bioch.ox.ac.uk bela.novak@bioch.ox.ac.uk.
  • 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.
Contributors
Submitter of the first revision: Frank Stefan Heldt
Submitter of this revision: Frank Stefan Heldt
Modellers: Frank Stefan Heldt

Metadata information

is (2 statements)
BioModels Database MODEL1703030000
BioModels Database BIOMD0000000700

isDescribedBy (1 statement)
PubMed 29463760

hasTaxon (1 statement)
Taxonomy Homo sapiens

hasPart (2 statements)
unknownQualifier (1 statement)
Mathematical Modelling Ontology Ordinary differential equation model


Curation status
Curated


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Model files

BIOMD0000000700_url.xml SBML L2V4 representation of Heldt2018 - Proliferation-quiescence decision in response to DNA damage 255.16 KB Preview | Download

Additional files

BIOMD0000000700-biopax2.owl Auto-generated BioPAX (Level 2) 73.01 KB Preview | Download
BIOMD0000000700-biopax3.owl Auto-generated BioPAX (Level 3) 123.03 KB Preview | Download
BIOMD0000000700.m Auto-generated Octave file 27.25 KB Preview | Download
BIOMD0000000700.pdf Auto-generated PDF file 293.00 KB Preview | Download
BIOMD0000000700.png Auto-generated Reaction graph (PNG) 813.82 KB Preview | Download
BIOMD0000000700.sci Auto-generated Scilab file 154.00 Bytes Preview | Download
BIOMD0000000700.svg Auto-generated Reaction graph (SVG) 143.38 KB Preview | Download
BIOMD0000000700.vcml Auto-generated VCML file 964.00 Bytes Preview | Download
BIOMD0000000700.xpp Auto-generated XPP file 19.87 KB Preview | Download
BIOMD0000000700_urn.xml Auto-generated SBML file with URNs 255.13 KB Preview | Download
MODEL1703030000.cps Annotated and curated model COPASI file (using version 4.23 Build 184) reproducing figure 1B of the reference publication. 321.33 KB Preview | Download
figure1.sedml SED-ML file reproducing figure 1B of the reference publication. 4.42 KB Preview | Download

  • Model originally submitted by : Frank Stefan Heldt
  • Submitted: Mar 3, 2017 11:25:00 AM
  • Last Modified: May 17, 2018 4:52:18 PM
Revisions
  • Version: 2 public model Download this version
    • Submitted on: May 17, 2018 4:52:18 PM
    • Submitted by: Frank Stefan Heldt
    • With comment: Current version of BIOMD0000000700
  • Version: 1 public model Download this version
    • Submitted on: Mar 3, 2017 11:25:00 AM
    • Submitted by: Frank Stefan Heldt
    • With comment: Original import of BIOMD0000000700

(*) You might be seeing discontinuous revisions as only public revisions are displayed here. Any private revisions unpublished model revision of this model will only be shown to the submitter and their collaborators.

Legends
: Variable used inside SBML models


Species
Reactions
Reactions Rate Parameters
RbE2f => pRb + E2f; Ce, Ca Cell*(kPhRbCd*Cd+kPhRbCe*Ce+kPhRbCa*Ca)*RbE2f kPhRbCe = 0.3; Cd = 0.65; kPhRbCd = 0.2; kPhRbCa = 0.3
aRc + P21 => iRc Cell*(kAsPcP21*aRc*P21-kDsPcP21*iRc) kDsPcP21 = 0.01; kAsPcP21 = 100.0
aPcna + pRc => aRc Cell*(kAsRcPc*aPcna*pRc-kDsRcPc*aRc) kDsRcPc = 0.001; kAsRcPc = 0.01
E2f => E2f + Ce Cell*kSyCe*E2f kSyCe = 0.01
iRc => iPcna; Dna Cell*piecewise(0, Dna < 1, piecewise(1*iRc, Dna > 1, 0.5*iRc)) []
Pr => ; C1 Cell*(kDePr+kDeCaC1*C1)*Pr kDePr = 1.0E-4; kDeCaC1 = 2.0
tE2f = E2f+RbE2f [] []
tC1 = C1+pC1+E1C1 [] []
Rb + E2f => RbE2f Cell*(kAsRbE2f*Rb*E2f-kDsRbE2f*RbE2f) kDsRbE2f = 0.005; kAsRbE2f = 5.0
=> E2f; E2f Cell*(kSyE2f+kSyE2fE2f*E2f/(jSyE2f+E2f)) kSyE2f = 0.03; jSyE2f = 0.2; kSyE2fE2f = 0.04
Curator's comment:
(added: 17 May 2018, 17:31:07, updated: 17 May 2018, 17:31:07)
Figure 1B of the reference publication was reproduced using Copasi 4.23 (Build 184)