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BIOMD0000000660 - Barr2017 - Dynamics of p21 in hTert-RPE1 cells

 

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Reference Publication
Publication ID: 28317845
Barr AR, Cooper S, Heldt FS, Butera F, Stoy H, Mansfeld J, Novák B, Bakal C.
DNA damage during S-phase mediates the proliferation-quiescence decision in the subsequent G1 via p21 expression.
Nat Commun 2017 Mar; 8: 14728
Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.  [more]
Model
Original Model: BIOMD0000000660.origin
Submitter: Frank Stefan Heldt
Submission ID: MODEL1607210001
Submission Date: 21 Jul 2016 08:15:17 UTC
Last Modification Date: 06 Dec 2017 16:32:10 UTC
Creation Date: 09 Jun 2016 17:37:08 UTC
Encoders:  Frank Stefan Heldt
   Emma Louise Fairbanks
   Rahuman Sheriff
set #1
bqbiol:hasProperty Pathway Ontology PW:0001317
Pathway Ontology PW:0001360
bqbiol:isDescribedBy PubMed 28317845
bqbiol:hasTaxon Taxonomy Homo sapiens
Notes
Barr2017 - Dynamics of p21 in hTert-RPE1 cells
This deteministic model reveals that a bistable switch created by Cdt2, promotes irreversible S-phase entry by keeping p21 levels low, prevents premature S-phase exit upon DNA damage

This model is described in the article:

Barr AR, Cooper S, Heldt FS, Butera F, Stoy H, Mansfeld J, Novák B, Bakal C.
Nat Commun 2017 Mar; 8: 14728

Abstract:

Following DNA damage caused by exogenous sources, such as ionizing radiation, the tumour suppressor p53 mediates cell cycle arrest via expression of the CDK inhibitor, p21. However, the role of p21 in maintaining genomic stability in the absence of exogenous DNA-damaging agents is unclear. Here, using live single-cell measurements of p21 protein in proliferating cultures, we show that naturally occurring DNA damage incurred over S-phase causes p53-dependent accumulation of p21 during mother G2- and daughter G1-phases. High p21 levels mediate G1 arrest via CDK inhibition, yet lower levels have no impact on G1 progression, and the ubiquitin ligases CRL4Cdt2 and SCFSkp2 couple to degrade p21 prior to the G1/S transition. Mathematical modelling reveals that a bistable switch, created by CRL4Cdt2, promotes irreversible S-phase entry by keeping p21 levels low, preventing premature S-phase exit upon DNA damage. Thus, we characterize how p21 regulates the proliferation-quiescence decision to maintain genomic stability.

This model is hosted on BioModels Database and identified by: BIOMD0000000660.

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.

Model
Publication ID: 28317845 Submission Date: 21 Jul 2016 08:15:17 UTC Last Modification Date: 06 Dec 2017 16:32:10 UTC Creation Date: 09 Jun 2016 17:37:08 UTC
Mathematical expressions
Reactions
Synthesis of p21 mRNAs Synthesis of p21 mRNAs by p53 Synthesis of cyclin mRNAs Synthesis of p53 mRNAs
Degradation of p21 mRNAs Degradation of cyclin mRNAs Degradation of p53 mRNAs Synthesis of p21
Degradation of p21 Synthesis of cyclins Degradation of cyclins Association and dissociation of CDK2:Cyclin and p21
Degradation of cyclin in CDK2:Cyclin:p21 complexes Degradation of p21 in CDK2:Cyclin:p21 complexes Import of active PCNA Export of active PCNA
Export of inactive PCNA Association and dissociation of PCNA and p21 Degradation of p21 in PCNA:p21 complexes Phosphorylation/priming of replication complexes
Dephosphorylation of replication complexes Association and dissociation of active PCNA and replication complexes Association and dissociation of inactive PCNA and replication complexes Association and dissociation of p21 and replication complexes
Degradation of p21 in inactive replication complexes Synthesis of DNA Dissassembly of RC Dissassembly of pRC
Dissassembly of aRC Dissassembly of iRC Synthesis of p53 Degradation of p53
Induction of DNA damage Induction of DNA damage by replication Repair of DNA damage  
Rules
Assignment Rule (variable: tP21) Assignment Rule (variable: tCy) Assignment Rule (variable: tPcna)  
Physical entities
Compartments Species
Cell MrnaP21 MrnaCy MrnaP53
P21 Cy CyP21
aPcna Rc pRc
aRc iRc Dna
Dam P53 Skp2
Cdt2 iPcna tP21
tCy tPcna  
Global parameters
kSyMrna kSyMrnaP53 kDeMrna kSyP21
kDeP21 kDeP21Cy kDeP21aRc kSyCy
kAsCyP21 kDsCyP21 kDeCy kDeCyCy
kImPc kExPc kPhRc kDpRc
jCy n kAsRcPc kDsRcPc
kAsPcP21 kDsPcP21 kSyDna kSyP53
kDeP53 jP53 kGeDam kGeDamArc
kReDam kReDamP53 jDam  
Reactions (35)
 
 Synthesis of p21 mRNAs  → [MrnaP21];  
 
 Synthesis of p21 mRNAs by p53 [P53] → [MrnaP21] + [P53];  
 
 Synthesis of cyclin mRNAs  → [MrnaCy];  
 
 Synthesis of p53 mRNAs  → [MrnaP53];  
 
 Degradation of p21 mRNAs [MrnaP21] → ;  
 
 Degradation of cyclin mRNAs [MrnaCy] → ;  
 
 Degradation of p53 mRNAs [MrnaP53] → ;  
 
 Synthesis of p21 [MrnaP21] → [MrnaP21] + [P21];  
 
 Degradation of p21 [P21] → ;   {Skp2} , {Cy} , {Cdt2} , {aRc}
 
 Synthesis of cyclins [MrnaCy] → [MrnaCy] + [Cy];  
 
 Degradation of cyclins [Cy] → ;   {Skp2} , {Cy}
 
 Association and dissociation of CDK2:Cyclin and p21 [Cy] + [P21] ↔ [CyP21];  
 
 Degradation of cyclin in CDK2:Cyclin:p21 complexes [CyP21] → [P21];   {Skp2} , {Cy}
 
 Degradation of p21 in CDK2:Cyclin:p21 complexes [CyP21] → [Cy];   {Skp2} , {Cy} , {Cdt2} , {aRc}
 
 Import of active PCNA  → [aPcna];  
 
 Export of active PCNA [aPcna] → ;  
 
 Export of inactive PCNA [iPcna] → [P21];  
 
 Association and dissociation of PCNA and p21 [aPcna] + [P21] ↔ [iPcna];  
 
 Degradation of p21 in PCNA:p21 complexes [iPcna] → [aPcna];   {Skp2} , {Cy} , {Cdt2} , {aRc}
 
 Phosphorylation/priming of replication complexes [Rc] → [pRc];   {Cy}
 
 Dephosphorylation of replication complexes [pRc] → [Rc];  
 
 Association and dissociation of active PCNA and replication complexes [aPcna] + [pRc] ↔ [aRc];  
 
 Association and dissociation of inactive PCNA and replication complexes [iPcna] + [pRc] ↔ [iRc];  
 
 Association and dissociation of p21 and replication complexes [aRc] + [P21] ↔ [iRc];  
 
 Degradation of p21 in inactive replication complexes [iRc] → [aRc];   {Skp2} , {Cy} , {Cdt2} , {aRc}
 
 Synthesis of DNA [aRc] → [aRc] + [Dna];  
 
 Dissassembly of RC [Rc] → ;   {Dna}
 
 Dissassembly of pRC [pRc] → ;   {Dna}
 
 Dissassembly of aRC [aRc] → [aPcna];   {Dna}
 
 Dissassembly of iRC [iRc] → [iPcna];   {Dna}
 
 Synthesis of p53 [MrnaP53] → [MrnaP53] + [P53];  
 
 Degradation of p53 [P53] → ;   {Dam}
 
 Induction of DNA damage  → [Dam];  
 
 Induction of DNA damage by replication [aRc] → [aRc] + [Dam];  
 
 Repair of DNA damage [Dam] → ;   {P53}
 
Rules (3)
 
 Assignment Rule (name: tP21) tP21 = P21+CyP21+iPcna+iRc
 
 Assignment Rule (name: tCy) tCy = Cy+CyP21
 
 Assignment Rule (name: tPcna) tPcna = aPcna+iPcna+aRc+iRc
 
Functions (14)
 
 Constant flux (irreversible) lambda(v, v)
 
 Function for Dissassembly of RC lambda(Dna, Rc, piecewise(0, Dna < 1, piecewise(1*Rc, Dna > 1, 0.5*Rc)))
 
 Function for Degradation of p21 lambda(Cdt2, Cy, P21, Skp2, aRc, kDeP21, kDeP21Cy, kDeP21aRc, (kDeP21+kDeP21Cy*Skp2*Cy+kDeP21aRc*Cdt2*aRc)*P21)
 
 Function for Degradation of cyclins lambda(Cy, Skp2, kDeCy, kDeCyCy, (kDeCy+kDeCyCy*Skp2*Cy)*Cy)
 
 Function for Degradation of cyclin in CDK2:Cyclin:p21 complexes lambda(Cy, CyP21, Skp2, kDeCy, kDeCyCy, (kDeCy+kDeCyCy*Skp2*Cy)*CyP21)
 
 Function for Degradation of p21 in CDK2:Cyclin:p21 complexes lambda(Cdt2, Cy, CyP21, Skp2, aRc, kDeP21, kDeP21Cy, kDeP21aRc, (kDeP21+kDeP21Cy*Skp2*Cy+kDeP21aRc*Cdt2*aRc)*CyP21)
 
 Function for Degradation of p21 in PCNA:p21 complexes lambda(Cdt2, Cy, Skp2, aRc, iPcna, kDeP21, kDeP21Cy, kDeP21aRc, (kDeP21+kDeP21Cy*Skp2*Cy+kDeP21aRc*Cdt2*aRc)*iPcna)
 
 Function for Phosphorylation/priming of replication complexes lambda(Cy, Rc, jCy, kPhRc, n, kPhRc*Cy^n/(jCy^n+Cy^n)*Rc)
 
 Function for Degradation of p21 in inactive replication complexes lambda(Cdt2, Cy, Skp2, aRc, iRc, kDeP21, kDeP21Cy, kDeP21aRc, (kDeP21+kDeP21Cy*Skp2*Cy+kDeP21aRc*Cdt2*aRc)*iRc)
 
 Function for Dissassembly of pRC lambda(Dna, pRc, piecewise(0, Dna < 1, piecewise(1*pRc, Dna > 1, 0.5*pRc)))
 
 Function for Dissassembly of aRC lambda(Dna, aRc, piecewise(0, Dna < 1, piecewise(1*aRc, Dna > 1, 0.5*aRc)))
 
 Function for Dissassembly of iRC lambda(Dna, iRc, piecewise(0, Dna < 1, piecewise(1*iRc, Dna > 1, 0.5*iRc)))
 
 Function for Degradation of p53 lambda(Dam, P53, jP53, kDeP53, kDeP53/(jP53+Dam)*P53)
 
 Function for Repair of DNA damage lambda(Dam, P53, jDam, kReDam, kReDamP53, (kReDam+kReDamP53*P53/(jDam+Dam))*Dam)
 
 Cell Spatial dimensions: 3.0  Compartment size: 1.0
 
 MrnaP21
Compartment: Cell
Initial concentration: 1.0
 
 MrnaCy
Compartment: Cell
Initial concentration: 1.0
 
 MrnaP53
Compartment: Cell
Initial concentration: 1.0
 
 P21
Compartment: Cell
Initial concentration: 0.72
 
 Cy
Compartment: Cell
Initial concentration: 0.4
 
 CyP21
Compartment: Cell
Initial concentration: 0.0
 
 aPcna
Compartment: Cell
Initial concentration: 0.5
 
 Rc
Compartment: Cell
Initial concentration: 1.0
 
 pRc
Compartment: Cell
Initial concentration: 0.0
 
 aRc
Compartment: Cell
Initial concentration: 0.0
 
 iRc
Compartment: Cell
Initial concentration: 0.0
 
 Dna
Compartment: Cell
Initial concentration: 0.0
 
 Dam
Compartment: Cell
Initial concentration: 0.0
 
 P53
Compartment: Cell
Initial concentration: 0.0
 
 Skp2
Compartment: Cell
Initial concentration: 1.0
Constant
 
 Cdt2
Compartment: Cell
Initial concentration: 1.0
Constant
 
 iPcna
Compartment: Cell
Initial concentration: 0.0
 
  tP21
Compartment: Cell
Initial concentration: 0.72
 
  tCy
Compartment: Cell
Initial concentration: 0.4
 
  tPcna
Compartment: Cell
Initial concentration: 0.5
 
Global Parameters (31)
 
 kSyMrna
Value: 0.02
Constant
 
 kSyMrnaP53
Value: 0.08
Constant
 
 kDeMrna
Value: 0.02
Constant
 
 kSyP21
Value: 0.0018
Constant
 
 kDeP21
Value: 0.0025
Constant
 
 kDeP21Cy
Value: 0.007
Constant
 
 kDeP21aRc
Value: 1.0
Constant
 
 kSyCy
Value: 0.005
Constant
 
 kAsCyP21
Value: 1.0
Constant
 
 kDsCyP21
Value: 0.05
Constant
 
 kDeCy
Value: 0.002
Constant
 
 kDeCyCy
Value: 2.0E-4
Constant
 
 kImPc
Value: 0.003
Constant
 
 kExPc
Value: 0.006
Constant
 
 kPhRc
Value: 0.1
Constant
 
 kDpRc
Value: 0.01
Constant
 
 jCy
Value: 1.8
Constant
 
 n
Value: 6.0
Constant
 
 kAsRcPc
Value: 0.01
Constant
 
 kDsRcPc
Value: 0.001
Constant
 
 kAsPcP21
Value: 100.0
Constant
 
 kDsPcP21
Value: 0.01
Constant
 
 kSyDna
Value: 0.007
Constant
 
 kSyP53
Value: 0.05
Constant
 
 kDeP53
Value: 0.05
Constant
 
 jP53
Value: 0.01
Constant
 
 kGeDam
Value: 0.001
Constant
 
 kGeDamArc
Value: 0.005
Constant
 
 kReDam
Value: 0.001
Constant
 
 kReDamP53
Value: 0.005
Constant
 
 jDam
Value: 0.5
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000660

Curator's comment: (updated: 28 Nov 2017 15:19:27 GMT)

Supplementary Figure 7a of the reference publication has been reproduced. The model as such reproduces the deterministic simulation of the mathematical model. Time courses of model components (Cdk2:Cyclin (blue), PCNA (purple), p21 (red) and aRC (green)) are shown relative to the G1/s transition. The simulations where performed using Copasi 4.19 (Build 140) and the plots were obtained using Matlab R2014b.

Additional file(s)
  • COPASI file:
    Simulations shown in supplementary Figure 7a of the reference publication can be reproduced using this COPASI file.
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