DNA damage during S-phase mediates the proliferation-quiescence decision in the subsequent G1 via p21 expression

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-damagin 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 onG1 progression and the ubiquitin ligases CRL4(Cdt2) and SCFSkp2 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.