p53 controls CDC7 levels to reinforce G1 cell cycle arrest upon genotoxic stress.
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.
a Wolfson Institute for Biomedical Research, Division of Medicine, University College London , London , UK.|b Division of Endocrinology, David Geffen School of Medicine, University of California Los Angeles , Los Angeles , CA , USA.
Slavica
S
Tudzarova
c Department of Pathology , UCL Cancer Institute, University College London , London , UK.
Paul
P
Mulholland
a Wolfson Institute for Biomedical Research, Division of Medicine, University College London , London , UK.
Ayona
A
Dey
c Department of Pathology , UCL Cancer Institute, University College London , London , UK.
Kai
K
Stoeber
a Wolfson Institute for Biomedical Research, Division of Medicine, University College London , London , UK.
Andrei L
AL
Okorokov
c Department of Pathology , UCL Cancer Institute, University College London , London , UK.|d Oncologica Ltd, The Science Village, Chesterford Research Park , Cambridge , UK.
Gareth H
GH
Williams
D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004249:DNA Damage; D015536:Down-Regulation / Q000235:genetics; D025461:Feedback, Physiological; D059585:G1 Phase Cell Cycle Checkpoints; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D035683:MicroRNAs; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D044767:Ubiquitin-Protein Ligases; C068619:CDC7 protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D017346:Protein Serine-Threonine Kinases
CDC7; CDK2; DNA damage; DNA replication; Fbxw7β; GSK3β; cell cycle; miRNA-192/215; p21; p53; protein degradation