Tudzarova, S;
Mulholland, P;
Dey, A;
Stoeber, K;
Okorokov, AL;
Williams, GH;
(2016)
p53 controls CDC7 levels to reinforce G1 cell cycle arrest upon genotoxic stress.
Cell Cycle
, 15
(21)
pp. 2958-2972.
10.1080/15384101.2016.1231281.
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Abstract
DNA replication initiation is a key event in the cell cycle, which is dependent on 2 kinases - CDK2 and CDC7. Here we report a novel mechanism in which p53 induces G1 checkpoint and cell cycle arrest by downregulating CDC7 kinase in response to genotoxic stress. We demonstrate that p53 controls CDC7 stability post-transcriptionally via miR-192/215 and post-translationally via Fbxw7β E3 ubiquitin ligase. The p53-dependent pathway of CDC7 downregulation is interlinked with the p53-p21-CDK2 pathway, as p21-mediated inhibition of CDK2-dependent phosphorylation of CDC7 on Thr376 is required for GSK3ß-phosphorylation and Fbxw7ß-dependent degradation of CDC7. Notably, sustained oncogenic high levels of active CDC7 exert a negative feedback onto p53, leading to unrestrained S-phase progression and accumulation of DNA damage. Thus, p53-dependent control of CDC7 levels is essential for blocking G1/S cell-cycle transition upon genotoxic stress, thereby safeguarding the genome from instability and thus representing a novel general stress response.
| Type: | Article |
|---|---|
| Title: | p53 controls CDC7 levels to reinforce G1 cell cycle arrest upon genotoxic stress |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1080/15384101.2016.1231281 |
| Publisher version: | http://doi.org/10.1080/15384101.2016.1231281 |
| Language: | English |
| Additional information: | © 2016 The Author(s). Published with license by Taylor & Francis© Slavica Tudzarova, Paul Mulholland, Ayona Dey, Kai Stoeber, Andrei L. Okorokov, and Gareth H. Williams This is an Open Access article distributed under the terms of the Creative Commons Attribution-Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted. |
| Keywords: | CDC7, CDK2, DNA damage, DNA replication, Fbxw7β, GSK3β, cell cycle, miRNA-192/215, p21, p53, protein degradation |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Wolfson Inst for Biomedical Research |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1515832 |
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