UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

p53 controls CDC7 levels to reinforce G1 cell cycle arrest upon genotoxic stress

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. Green open access

[img]
Preview
Text
okorokov_11-7-2016_p53 contro.pdf

Download (2MB) | Preview

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
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 > Cancer Institute > Research Department of Oncology
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
Downloads since deposit
128Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item