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

This new discovery in relation to the molecular circuitry regulation the G1 cell cycle checkpoint provides a unique insight into why the new anti-cancer approach proposed using Cdc7 targeted anti-cancer therapies can act as powerful tumour killing agents but do not affect the normal cells of the body thereby circumventing the toxicity associated with conventional chemotherapy.

DNA replication initiation is a key event in the cell cycle, which is dependent on two 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.

Authors: Tudzarova S, Mulholland P, Dey A, Stoeber K, Okorokov AL, Williams GH