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

Slavica Tudzarova1,2, Paul Mulholland3, Ayona Dey1

  • 1a Wolfson Institute for Biomedical Research, Division of Medicine, University College London , London , UK.

Cell Cycle (Georgetown, Tex.)
|September 10, 2016
PubMed

Insights

The tumor suppressor p53 halts cell cycle progression during genotoxic stress by reducing CDC7 kinase levels. This novel pathway involves microRNAs and E3 ligase, safeguarding genomic stability.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • DNA replication initiation is regulated by CDK2 and CDC7 kinases.
  • Cell cycle checkpoints are crucial for preventing genomic instability.

Purpose of the Study:

  • To elucidate a novel mechanism by which p53 induces cell cycle arrest in response to genotoxic stress.
  • To investigate the role of CDC7 kinase regulation in the p53-mediated G1 checkpoint.

Main Methods:

  • Post-transcriptional regulation by miR-192/215.
  • Post-translational regulation via Fbxw7β E3 ubiquitin ligase.
  • Analysis of the interplay between p53, p21, CDK2, and CDC7 pathways.

Main Results:

  • p53 downregulates CDC7 kinase stability through both post-transcriptional and post-translational mechanisms.
  • p21 inhibits CDK2-dependent phosphorylation of CDC7, facilitating its degradation.
  • High CDC7 levels create a negative feedback loop on p53, promoting S-phase progression and DNA damage.

Conclusions:

  • p53-dependent control of CDC7 is essential for blocking G1/S transition under genotoxic stress.
  • This pathway represents a novel general stress response mechanism.
  • Maintaining genomic stability is a key function of the p53-CDC7 regulatory axis.
Keywords:
CDC7CDK2DNA damageDNA replicationFbxw7βGSK3βcell cyclemiRNA-192/215p21p53protein degradation

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