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DNA damage during S-phase mediates the proliferation-quiescence decision in the subsequent G1 via p21 expression
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DNA damage during S-phase mediates the proliferation-quiescence decision in the subsequent G1 via p21 expression
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Journal Article
DNA damage during S-phase mediates the proliferation-quiescence decision in the subsequent G1 via p21 expression
2017
Overview
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 CRL4
Cdt2
and SCF
Skp2
couple to degrade p21 prior to the G1/S transition. Mathematical modelling reveals that a bistable switch, created by CRL4
Cdt2
, 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.
Cell cycle arrest after DNA damage is achieved by the expression of the CDK inhibitor p21. Here the authors show that spontaneous DNA damage incurred in unperturbed cell cycles, leads to cell populations exhibiting a bistable state, with p53 and p21 regulating the proliferation-quiescence decision.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/109
/ 13/89
/ 14/19
/ 14/63
/ 38/35
/ 96/31
/ Cell Cycle Checkpoints - genetics
/ Cell Proliferation - genetics
/ Cyclin-Dependent Kinase Inhibitor p21 - genetics
/ Cyclin-Dependent Kinase Inhibitor p21 - metabolism
/ DNA
/ Green Fluorescent Proteins - genetics
/ Green Fluorescent Proteins - metabolism
/ Humanities and Social Sciences
/ Humans
/ Kinases
/ Proteins
/ Science
