Heldt2018 - Proliferation-quiescence decision in response to DNA damage
View the 2018-08 Model of the Month entry for this model
This model is described in the 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.
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.
-
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.
Submitter of this revision: Frank Stefan Heldt
Modellers: Frank Stefan Heldt
Metadata information
isDescribedBy (1 statement)
hasTaxon (1 statement)
hasPart (2 statements)
unknownQualifier (1 statement)
Connected external resources
SBGN view in Newt Editor
| Name | Description | Size | Actions |
|---|---|---|---|
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
- Submitted on: May 17, 2018 4:52:18 PM
- Submitted by: Frank Stefan Heldt
- With comment: Current version of BIOMD0000000700
-
Version: 1
- 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
of this model will only be shown to the submitter and their collaborators.
: Variable used inside SBML models
| Species | Initial Concentration/Amount |
|---|---|
| RbE2f Retinoblastoma-like protein 2 ; protein-containing complex ; Transcription factor E2F1 ; inactive |
0.0 mmol |
| P21 Cyclin-dependent kinase inhibitor 1 |
0.6 mmol |
| aPcna Proliferating cell nuclear antigen ; active |
0.5 mmol |
| Ce Cyclin-dependent kinase 2 ; protein-containing complex ; G1/S-specific cyclin-E1 ; active |
0.5 mmol |
| iRc Pre-Replication Complex ; inactive |
0.0 mmol |
| Pr | 0.5 mmol |
| tE2f Transcription factor E2F1 |
0.0 mmol |
| tC1 anaphase-promoting complex |
1.0 mmol |
| Rb Retinoblastoma-like protein 2 |
0.0 mmol |
| E2f Transcription factor E2F1 ; active |
0.0 mmol |
| 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 |
(added: 17 May 2018, 17:31:07, updated: 17 May 2018, 17:31:07)