ArticleCell cycle (Georgetown, Tex.)2016
p53 controls CDC7 levels to reinforce G1 cell cycle arrest upon genotoxic stress.
Article in Cell cycle (Georgetown, Tex.), 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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17 citing papers in PubMed, 22 citations in OpenAlex.
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- Coordination of miR-192 and miR-22 in p53-Mediated Cell Fate Decision.International journal of molecular sciences · 2019Article
- A kinase inhibitor screen identifies a dual cdc7/CDK9 inhibitor to sensitise triple-negative breast cancer to EGFR-targeted therapy.Breast cancer research : BCR · 2019Article
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- Comprehensive analysis of differential expression profiles reveals potential biomarkers associated with the cell cycle and regulated by p53 in human small cell lung cancer.Experimental and therapeutic medicine · 2018Article
- CDC7-dependent transcriptional regulation of RAD54L is essential for tumorigenicity and radio-resistance of glioblastoma.Translational oncology · 2018Article
- Role of MCM2-7 protein phosphorylation in human cancer cells.Cell & bioscience · 2018Review
- Overexpression of Topoisomerase 2-Alpha Confers a Poor Prognosis in Pancreatic Adenocarcinoma Identified by Co-Expression Analysis.Digestive diseases and sciences · 2017Article
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- A novel p53-Cdc7 link induced by genotoxic stress.Cell cycle (Georgetown, Tex.) · 2017Article
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6 authors at 2 institutions in 2 countries.
Funding
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.
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