BioModelsapplication/xmlhttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000660?filename=BIOMD0000000660.pdfhttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000660?filename=BIOMD0000000660-biopax2.owlhttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000660?filename=BIOMD0000000660-biopax3.owlhttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000660?filename=BIOMD0000000660_url.xmlhttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000660?filename=BIOMD0000000660_urn.xmlhttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000660?filename=MODEL1607210001.cpshttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000660?filename=BIOMD0000000660.xpphttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000660?filename=BIOMD0000000660.scihttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000660?filename=BIOMD0000000660.mhttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000660?filename=BIOMD0000000660.pnghttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000660?filename=BIOMD0000000660.vcmlprimaryOK200Frank Stefan HeldtManually curatedL2V4https://www.ebi.ac.uk/biomodels/BIOMD000000066028317845falseBioModelsSBMLModelsBarr2017 Dynamics of p21 in hTert RPE1 cells2017MODEL1607210001Barr AR, Cooper S, Frank Stefan Heldt, Butera F, Stoy H, Mansfeld J, Novák B, Bakal CBarr AR28317845,
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.. null, 8.
Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.st.heldt@gmail.comUniversity of OxfordBIOMD0000000660Following 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 CRL4<sup>Cdt2</sup> and SCF<sup>Skp2</sup> couple to degrade p21 prior to the G1/S transition. Mathematical modelling reveals that a bistable switch, created by CRL4<sup>Cdt2</sup>, 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.DNA damage during S-phase mediates the proliferation-quiescence decision in the subsequent G1 via p21 expression.Barr Alexis R AR, Cooper Samuel S, Heldt Frank S FS, Butera Francesca F, Stoy Henriette H, Mansfeld Jörg J, Novák Béla B, Bakal Chris Cl(2)04454, DmelCG1772, Cyclin-dependent kinase inhibitor 1A (P21, WEX9, cip1, CIB1, pp21, TCTP, P21, Kras2, 21 kDa polypeptide, Trt, p21[dacapo], c-Ki-ras, cdi4, Cip1), p21Cip1, p21CIP1, p21, p23, CG1772, Cdi4, CDI4, Cell., p27, Decapo, Protein Cdkn1a, CAP20, SDI1, 0610011M09Rik, P21 protein, Cdkn1, E(Sev-CycE)2B, Melanoma differentiation-associated protein 6, CIP1, SIIR, p21WAF, D4S234, Waf1, WAF1, CDKI, CDKN2B, NEEP21, Dac, p27[Dap], Melanoma differentiation-associated protein, dacapo/cyclin-dependent kinase interactor 4, p16Xic2, MDA-6, Dap, P15, D4S234E, CDK-interacting protein 1, BC011290, CDKN1, mda6l(2)k06503, dp53, Cyclin-dependent kinase inhibitor 1A (P21, tumor suppressor, pp21, CDK, neuronal cdc2-like kinase activity, FON1, Elevated, catalytic subunit activity, High Risk, DCAF2, p21[dacapo], sci, FLORAL ORGAN NUMBER 1, DmelCG9772, G1/S Transition, dmTAF[[II]]230, cell cycle regulator, ramp, Microsatellite Instability-High, Prior Medication Usage, cdk, bbl, HOW, How, Response Inhibition, RAMP, Live File, Fs(3)Hor, tumor suppressor p53, MSI-H, cyclin-dependent protein kinase, Progression, xskp2, thymus nucleic acid, cellular quiescence, TFIID TAF250, BCC7, cel, IL17BR, beta-Tub6D, dmp53, Bdr, Entry, stru, T, 1422/04, Kitl, CG9148, l(3)S053606, NTef2, p21WAF, Mast cell growth factor, D17Mit170, SNAP-25, Ligase, G1 Block, Dp53, regulation of cell cycle progression, p16Xic2, Role Concepts, stem cell factor receptor ligand, High-Frequency Microsatellite Instability, CG17117, sev1, p50/tubulin, CG10873, dTAF[[II]]230, Followed By, cip1, Creator, TAF200, quiescence, Tl3, CEP52, Tl2, Fs(3)Sz11, Cdk-activating protein kinase activity, cdk-activating kinase activity, Role Concept, arrest of mitotic cell cycle progression, Maintenance, Tumor Progression, Disease Progression, modulation of cell cycle progression, Role, GENA70, bfy, External, desoxyribose nucleic acid, Created By, HTH, Hth, Ubiq, Mathematics, Cancer Disease Progression, Outside, Stem cell factor, Cdkn1, CG3401, beta3Tub, beta3TUB, pooled, Coupled, Cdk4/6, CIP1, Waf1, l2dtl, WAF1, Genomic, live, Leading, DTB3, CDKN2B, cyclin-dependent kinase 6 activity, stem cell factor, Taf250, Proliferation, IPSS-R High Risk, ds DNA, MDA-6, CG2684, G0 phase, l(2)0671, bhy, DNA, Ionizing Radiations, G1 Arrest, E430016J11Rik, CG31325, BC011290, Gb, CDKN1, TAF230, FLORAL DEFECTIVE 10, cyclin-dependent protein kinase inhibitor activity, beta[[3]]-Tub, Microsatellite Instability High, DmelCG17117, l(2)04454, cyclin D-cdk6 kinase activity, advanced, dtl-b, Clo, DNS, (Deoxyribonucleotide)n, Conditional, antigen NY-CO-13, TCTP, SLF, Slf, cyclin-dependent kinase inhibitor, Contingency, 143391_i_at, ATP Dependent Proteolysis Factor 1, SUPERMAN, beta3 TU, LFS1, Inhibition, l(3)05745, Human, cdi4, MOTHER, Live, Deoxyribonucleic Acid, Dressing (includes tying shoes, CDK inhibitor, Cdi4, CDI4, G1 to S Transition Process, anon-EST:Liang-2.13, Higher, Inhibiting, down-regulation of cyclin-dependent protein kinase activity, Injury, dTAF[[II]]250, Bathes with Help, disease progression, cell, proliferating, absent from organism, cyclin dependent protein kinase inhibitor activity, Double Stranded, Deoxyribonucleic acid, Coupling, CDKI, dTAF250, 40S ribosomal protein S27a, Con, cdk4, Unclear State of Matter, control of cell cycle progression, Suppressor Device, regulation of progression through cell cycle, Mathematical, genome, blz, beta[[3]]-tubulin, Expression, (Deoxyribonucleotide)m, CDK4, protein tagging activity, l(2)05428, negative regulation of cell cycle arrest, anon-EST:Posey14, cell cycle modulation, SINGLE, HIGH, Dmbeta3, cou, DNAn+1, hematopoietic growth factor KL, Preceding, prac, beta3t, Trt, BG:DS00004.13, Synaptosomal-associated 25 kDa protein, c-Ki-ras, qkr, l(3)S090417, negative regulation of cyclin-dependent protein kinase activity, Cell, Conditionality, Concept, dTAF230, positive regulation of cell cycle arrest, Ubiquitin A-52 residue ribosomal protein fusion product 1, Lr, Have, Ubiquitin-related 2, p53/tubulin, KH93F, Bathing self with help, TAF[[II]]250/230, prior drugs, cyclin-A associated kinase activity, intrinsic catalyst activity, IPSS-R Risk Category High, Before, Taf[[II]]250, Genotoxic Stress, CG33336, covalent modifier, Single Person, progression, cdc2 kinase activity, 0610011M09Rik, D-p53, Dm-P53, beta3, Suppressor, SIIR, Lds, dtl, mitotic cell cycle arrest, Ionizing Radiation, Tub, High, 60S ribosomal protein L40, protein tag, betatub60D, MGF, Mgf, Stress, Dependent Bathing, Desoxyribonukleinsaeure, Bra, Pk53C, Solitary, Ubiquitin-related, Alone, CDK activity, WEX9, CRL4, EVI27, 21 kDa polypeptide, cdk4/6, betaTub3, Highly, SKP2, Tp53, contrasted, DMP53, PRIOR, Roles, SUP, Concepts, Dmp53, Inhibitory, Prior, l(3)j5D5, TP53, gene expression, 24B, 1323/07, me75, DmelCG2684, High Mobility Protein 20, S-phase, P21 protein, DTL83, SF, E(Sev-CycE)2B, Ubiquitin-related 1, DmP53, Melanoma differentiation-associated protein 6, Super protein, CG10293, D4S234, sp, T1, CDT2, Cdt2, dcaf2, Call, APF-1, l(3)j5B5, B3t, Negative Regulation of G1 Phase, DmelCG3401, Had, Subsequent, Decision, dCdk4, phosphoprotein p53, cdt2, Double-Stranded DNA, P15, Soluble KIT ligand, deoxyribonucleic acids, DNAn, FBXL1, D4S234E, Sl, Has, Dependent Dressing, Lower, Pre, 0904/17, steel factor, CG9772, P21, D-type cyclin kinase activity, 153298_at, Ionizing, Double-Stranded, TAFII-250, TAF250/230, sKITLG, 3t, (Deoxyribonucleotide)n+m, Gene Expression, Revised International Prognostic Scoring System for Myelodysplastic Syndrome High Risk Category, TAFII250, SZ1, p21, p23, precocious, p27, LOWER, cyclin-dependent kinase-2 activity, Tub60D, CAP20, Ubiquitin, DNA Injury, High Mitosis-Karyorrhexis Index, BEST:CK02682, DNA Injuries, beta-tub, Maintain, cyclin-dependent kinase activity, SHEP7, absence, down regulation of cyclin-dependent protein kinase activity, mast cell growth factor, Genomic., prior_drugs, cessation of cell cycle, IPSS High Risk, L2DTL, DmelCG33336, ATP:cyclin phosphotransferase activity, Human Ubiquitin, cdt2-b, cdt2-a, CG17603, TAF[[II]], early, cyclin D-dependent kinase activity, Dependent for Toilet Use, IPSS Risk Category High, Lowering, Kitlg, hth1, CDK4/6, DmelCG9148, KL-1, Genotoxic, hth2, p27[Dap], Melanoma differentiation-associated protein, Expressed, SR3-5, Horka, P53, regulation of cell cycle arrest, p45, p44, Fs(3)Horka, KITLG, anon-EST:Liang-2.39, Unclear, CG11295, cell cycle regulation, betaTub, Contingent, Proliferating, FBL1, KIT binding, DmelCG1772, d230, p50, CIB1, Math, P62, p53, Kras2, arrest of cell cycle progression, dTAFII250, Synthetases, FPH2, Pk?7, fastening fasteners) with help, Ubiquitin carboxyl extension protein 80, EfW1, Ximpact, inhibition of cyclin-dependent protein kinase activity, dependent, Deoxyribonucleic acids, International Prognostic Scoring System for Myelodysplastic Syndrome High Risk Category, p21Cip1, p21CIP1, Value Above Reference Range, dmTAF1, termination of cell cycle, Taf230, HMG-20, DCB-45, Switch, Low, DmF2, Next, ubiquitin-like protein modifier, Externally, Decapo, SDI1, TAF250, lod, Taf200, Couple, clone 2.13, l(3)s2612, negative regulation of CDK activity, CG5072, D.m.BETA-60D, cyclin E kinase activity, cyclin-dependent protein kinase activity, High Level, Mother, Taf1p, FLB1, downregulation of cyclin-dependent protein kinase activity, cyclin-dependent kinase-4 activity, Mif1, Trp53, NEEP21, Dac, Following, dacapo/cyclin-dependent kinase interactor 4, ubiquitin, Switch Device, betaTub60C, DmelCG10293, Dap, beta3-tubulin, TRP53, TAF, Switch/Relay, CDK-interacting protein 1, Possess, beta-Tub60D, TAF[[II]]250, Dm-HTH, Dependent, cell cycle arrest, DmelCG11295, clone 2.39, BETA 60D, beta3-Tub, cell cycle quiescence, l(3)84Ab, Reside, impact-a, Xp53, Exogenous, l(2)s4639, Cip1), Daughter, SCFR binding, p230, Extramural, CG1772, Synthetase, IL17RH1, TFIID, beta[[3]] tubulin, ds-DNA, ATP-Dependent Proteolysis Factor 1, Protein Cdkn1a, DmCdk4, who, Radiations, Lowered, TAF[[II]]230, DNA Lesion, beta60C, l(3)86Ca, TAF[II]250, FLO10, Who/How, DmelCG5072, MSI high, HERP, Dresses with Help, 8-6, DNA Lesions, Meis1, DmelCG17603, Cancer Progression, Only, c-Kit ligand, qkr[93F], BEFORE, Single, cyclin dependent kinase inhibitor, SCF, Genome, l(2)sh0671, RWDD5, CK02682, mda6, TAF1extent, l(2)k06503, Cyclin-dependent kinase inhibitor 1A (P21, dp53, Public Sectors, pp21, CDK, neuronal cdc2-like kinase activity, fond, AUTSX5, catalytic subunit activity, DCAF2, p21[dacapo], CycEI, dmTAF[[II]]230, ramp, Anniversary, cdk, bbl, RAMP, Public Enterprise, Fs(3)Hor, tumor suppressor p53, cyclin-dependent protein kinase, thymus nucleic acid, cellular quiescence, TFIID TAF250, BCC7, cel, cell process disease, tumor disease, beta-Tub6D, dmp53, T, 1422/04, NTef2, p21WAF, D17Mit170, Ligase, Dp53, p16Xic2, Role Concepts, NOVh, sev1, CG17117, p50/tubulin, CG10873, dTAF[[II]]230, cip1, completeness, acid, TAF200, quiescence, Tl3, 2-(acetylamino)-2-deoxy-, Cyc E, Tl2, CEP52, Fs(3)Sz11, Fsrg1, Cdk-activating protein kinase activity, Special Events, RING3, cdk-activating kinase activity, Role Concept, BG:DS07108.3, Public Domain, FSRG1, Role, Domains, bfy, Nucl, l(2)05206, desoxyribose nucleic acid, HTH, Hth, Ubiq, Acid, Special Event, Plxn1, Cdkn1, CG3401, beta3Tub, beta3TUB, pooled, Cdk4/6, CIP1, Waf1, l2dtl, mKIAA4053, WAF1, tumour disease, DTB3, CDKN2B, cyclin-dependent kinase 6 activity, Sector, Taf250, Proliferation, (5Z, ds DNA, MDA-6, CG2684, G0 phase, l(2)0671, bhy, DNA, other neoplasm, E430016J11Rik, BC011290, Fsrg-1, CG31325, CDKN1, TAF230, D0Nds28, NAT, Nat, cyclin-dependent protein kinase inhibitor activity, beta[[3]]-Tub, l(2)04454, DmelCG17117, advanced, cyclin D-cdk6 kinase activity, Sectors, dtl-b, D17H6S113E, cycline, DNS, (Deoxyribonucleotide)n, TCTP, antigen NY-CO-13, cyclin-dependent kinase inhibitor, DmcyclinE, alpha-L-N-acetyltalosaminuronic acid, 143391_i_at, ATP Dependent Proteolysis Factor 1, Copyrights, beta3 TU, FSH, LFS1, l(3)05745, Human, cdi7, cdi4, cyclinE, Deoxyribonucleic Acid, D1Nds28, Cdi7, CDI7, Cdi4, CDI4, CDK inhibitor, anon-EST:Liang-2.13, neoplasm, Enterprises, MAR, down-regulation of cyclin-dependent protein kinase activity, Injury, dTAF[[II]]250, cell, proliferating, absent from organism, cyclin dependent protein kinase inhibitor activity, Double Stranded, Events, tumour, Deoxyribonucleic acid, IGFBP9, DmcycE, Public Enterprises, CDKI, dTAF250, 40S ribosomal protein S27a, cdk4, beta[[3]]-tubulin, (Deoxyribonucleotide)m, CDK4, Enterprise, protein tagging activity, Saeure, l(2)05428, Dmbeta3, cou, DNAn+1, prac, beta3t, Trt, BG:DS00004.13, c-Ki-ras, negative regulation of cyclin-dependent protein kinase activity, Cell, dTAF230, Concept, Anniversaries, neoplastic growth, Lr, Ubiquitin A-52 residue ribosomal protein fusion product 1, l(2)k02514, DmCycE, Ubiquitin-related 2, Public, AW228947, p53/tubulin, TAF[[II]]250/230, cyclin-A associated kinase activity, intrinsic catalyst activity, Taf[[II]]250, Genotoxic Stress, CG33336, covalent modifier, C23, l(2)k02602, cdc2 kinase activity, Saeuren, 0610011M09Rik, D-p53, Dm-P53, beta3, SIIR, Lds, disease of cellular proliferation, dtl, Tub, D-CycE, 60S ribosomal protein L40, protein tag, betatub60D, Stress, EG:95B7.8, Bra, Desoxyribonukleinsaeure, Pk53C, 2600013D04Rik, Ubiquitin-related, alpha-L-2-N-acetylamino-2-desoxytaluronic acid, CDK activity, 11alpha, WEX9, TalANAc, neoplasia, 21 kDa polypeptide, cdk4/6, CCN3, betaTub3, QM, Tp53, DMP53, Ccne, Roles, Concepts, Dmp53, fs(1)M104, TP53, 1323/07, me75, DmelCG2684, High Mobility Protein 20, S-phase, neoplasm (disease), Public Domains, P21 protein, DTL83, E(Sev-CycE)2B, Ubiquitin-related 1, DmP53, Melanoma differentiation-associated protein 6, D4S234, T1, CDT2, Cdt2, IBP-9, dcaf2, APF-1, 13E, B3t, reaction, DmelCG3401, Dedications, dCdk4, phosphoprotein p53, cdt2, Double-Stranded DNA, P15, tumor, deoxyribonucleic acids, DNAn, D4S234E, Event, IRF-1, P21, D-type cyclin kinase activity, neoplastic disease, Double-Stranded, TAFII-250, TAF250/230, br37, 3t, (Deoxyribonucleotide)n+m, TAFII250, p21, p23, precocious, p27, NOV, PlexA1, cyclin-dependent kinase-2 activity, Tub60D, Domain, CAP20, Ubiquitin, DNA Injury, DNA Injuries, beta-tub, cyclin-dependent kinase activity, absence, down regulation of cyclin-dependent protein kinase activity, acide, L2DTL, DmelCG33336, cdt2-b, ATP:cyclin phosphotransferase activity, Human Ubiquitin, acids, nov, cdt2-a, acido, 15S)-, CG17603, TAF[[II]], fs(1)Y[b], early, cyclin D-dependent kinase activity, hth1, CDK4/6, Genotoxic, hth2, l35Dd, p27[Dap], Melanoma differentiation-associated protein, Horka, SR3-5, C130088N23Rik, P53, Fs(3)Horka, p44, DXS648E, CG11295, betaTub, Proliferating, DmelCG1772, B530004O11Rik, d230, alpha-L-Talopyranuronic acid, YB, CIB1, p50, Kras2, p53, dTAFII250, Synthetases, cycE, Pk?7, Ubiquitin carboxyl extension protein 80, Special, EfW1, Ximpact, inhibition of cyclin-dependent protein kinase activity, l(2)br37, Deoxyribonucleic acids, CYCLE, p21Cip1, p21CIP1, Yb, dmTAF1, Taf230, HMG-20, Low, DmF2, ubiquitin-like protein modifier, Decapo, CG2706, SDI1, TAF250, lod, Taf200, CYCE, clone 2.13, negative regulation of CDK activity, CG5072, D.m.BETA-60D, DmelCG3938, CyclE, cyclin E kinase activity, cyclin-dependent protein kinase activity, 3938, Taf1p, Ring3, downregulation of cyclin-dependent protein kinase activity, l(2)k05007, cyclin-dependent kinase-4 activity, dm-cycE, Trp53, Abstract, NEEP21, Dac, L10, dacapo/cyclin-dependent kinase interactor 4, ubiquitin, betaTub60C, Dap, beta3-tubulin, TRP53, TAF, CDK-interacting protein 1, beta-Tub60D, TAF[[II]]250, Dm-HTH, DmelCG11295, DmelCG2706, BETA 60D, beta3-Tub, cell cycle quiescence, DXS648, l(3)84Ab, impact-a, Xp53, l(2)s4639, Cip1), IGFBP-9, p230, CG1772, Synthetase, TFIID, mKIAA4005, CyeE, beta[[3]] tubulin, ds-DNA, ATP-Dependent Proteolysis Factor 1, Protein Cdkn1a, DmCdk4, Data Base, Radiations, D6S113E, TAF[[II]]230, Rnf3, RNF3, Frg-1, l(2)35Dd, DNA Lesion, beta60C, l(3)86Ca, TAF[II]250, DmelCG5072, 8-6, DNA Lesions, Meis1, DmelCG17603, Public., cyclin dependent kinase inhibitor, CG3938, l(2)sh0671, RWDD5, mda6, TAF1Proliferating, l(2)04454, DmelCG1772, Cyclin-dependent kinase inhibitor 1A (P21, Followed By, WEX9, cip1, CIB1, pp21, TCTP, P21, Kras2, 21 kDa polypeptide, cell cycle quiescence, Trt, p21[dacapo], quiescence, c-Ki-ras, cdi4, Gene Expression, Cip1), p21Cip1, p21CIP1, p21, p23, CG1772, Cdi4, CDI4, p27, Next, Decapo, Protein Cdkn1a, CAP20, SDI1, DNA Injury, Genotoxic Stress, DNA Injuries, Injury, cellular quiescence, S-phase, proliferating, 0610011M09Rik, P21 protein, DNA Lesion, Cdkn1, E(Sev-CycE)2B, Melanoma differentiation-associated protein 6, CIP1, SIIR, p21WAF, D4S234, Waf1, WAF1, CDKI, Call, gene expression., DNA Lesions, CDKN2B, Genotoxic, NEEP21, Dac, Following, p27[Dap], Melanoma differentiation-associated protein, Expressed, Proliferation, Subsequent, dacapo/cyclin-dependent kinase interactor 4, p16Xic2, Stress, Decision, MDA-6, G0 phase, Dap, P15, Expression, DNA, D4S234E, CDK-interacting protein 1, BC011290, CDKN1, mda6falseBarr2017 - Dynamics of p21 in hTert-RPE1 cells
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:
DNA damage during S-phase
mediates the proliferation-quiescence decision in the
subsequent G1 via p21 expression.
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.
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To cite BioModels Database, please use:
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2017-12-062016-06-092016-07-21BIOMD000000066028317845NCIT_C16507CHEBI:33699CHEBI:16991PW:0001360MODEL1607210001BIOMD0000000660PATO:0002354PATO:0002355GO:0036387GO:0009299GO:0006402GO:0045727GO:0030163GO:0006461GO:0043241GO:0006606GO:0006611GO:0016310GO:0016311GO:00007319606BTO:0004790OMIT_0005506OMIT_0005517P38936P24864P78396P04637P12004Q13309Q9NZJ0P24941