Journal article
DNA damage during S-phase mediates the proliferation-quiescence decision in the subsequent G1 via p21 expression
- 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 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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 1.6MB, Terms of use)
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- Publisher copy:
- 10.1038/ncomms14728
Authors
+ German Research Foundation
More from this funder
- Funding agency for:
- Mansfeld, J
- Grant:
- MA 5831/1-1
+ Biotechnology and Biological Sciences Research Councils
More from this funder
- Funding agency for:
- Novák, B
- Bakal, C
- Grant:
- BB/M00354X/1
- BB/M00354X/1
- Publisher:
- Nature Publishing Group
- Journal:
- Nature Communications More from this journal
- Volume:
- 8
- Pages:
- 14728
- Publication date:
- 2017-03-20
- Acceptance date:
- 2017-01-26
- DOI:
- EISSN:
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2041-1723
- Language:
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English
- Keywords:
- Pubs id:
-
pubs:686688
- UUID:
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uuid:4ec77933-5289-4c3e-9994-18344334f5c4
- Local pid:
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pubs:686688
- Source identifiers:
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686688
- Deposit date:
-
2017-03-25
Terms of use
- Copyright holder:
- © Barr, et al 2017
- Copyright date:
- 2017
- Notes:
-
This work is licensed under a Creative Commons Attribution 4.0
International License. The images or other third party material in this
article are included in the article’s Creative Commons license, unless indicated otherwise
in the credit line; if the material is not included under the Creative Commons license,
users will need to obtain permission from the license holder to reproduce the material.
To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
- Licence:
- CC Attribution (CC BY)
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