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Barr2017 - Dynamics of p21 in hTert-RPE1 cells


ABSTRACT: 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. 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.

SUBMITTER: Frank Stefan Heldt  

PROVIDER: BIOMD0000000660 | BioModels | 2016-06-09

REPOSITORIES: BioModels

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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 C  

Nature communications 20170320


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-  ...[more]

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