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-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 CRL4Cdt2and SCFSkp2couple 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.
Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
Alexis R
AR
Barr
Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.|Department of Computational Systems Medicine, Imperial College, South Kensington Campus, London SW7 2AZ, UK.
Samuel
S
Cooper
Department of Biochemistry, OCISB, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
Frank S
0000-0002-9276-5013
FS
Heldt
Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
Francesca
F
Butera
Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
Henriette
H
Stoy
Cell Cycle, Biotechnology Centre, TU Dresden, 01307 Dresden, Germany.
Jörg
J
Mansfeld
Department of Biochemistry, OCISB, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
Béla
B
Novák
Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
Chris
0000-0002-0413-6744
C
Bakal
D059447:Cell Cycle Checkpoints / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation / Q000235:genetics*; D058948:Cell Tracking / Q000379:methods; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics* / Q000378:metabolism; D004249:DNA Damage; D016193:G1 Phase / Q000235:genetics*; D055786:Gene Knockout Techniques; D042822:Genomic Instability; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018613:Microscopy, Confocal; D016196:S Phase / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; D049452:Green Fluorescent Proteins