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Functions of mammalian Cdc7 kinase in initiation/monitoring of DNA replication and development

Jung Min Kim1, Masayuki Yamada, Hisao Masai

  • 1Department of Cell Biology, Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8613, Japan.

Mutation Research
|December 4, 2003
PubMed

Insights

Cdc7 kinase is crucial for DNA replication origin firing and continuation of DNA synthesis in mouse embryonic stem cells. Its loss triggers DNA replication checkpoints, p53 activation, and apoptosis, ensuring genetic integrity.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • Cdc7 kinase is vital for initiating DNA replication by phosphorylating replication complex components.
  • It also participates in S phase checkpoint signaling pathways involving ATR and Chk1 kinases.

Purpose of the Study:

  • To investigate the role of Cdc7 kinase in DNA replication and cell cycle control in mammalian cells, specifically mouse embryonic stem cells.
  • To understand the consequences of Cdc7 inactivation on DNA synthesis, checkpoint activation, and cell fate.

Main Methods:

  • Conditional inactivation of Cdc7 in mouse embryonic stem cells.
  • Analysis of DNA synthesis, cell cycle progression, DNA damage response markers (Rad51 foci), and checkpoint activation (Cdc2 kinase inhibition).
  • Assessment of p53 activation and apoptosis induction.

Main Results:

  • Cdc7 inactivation in mouse ES cells caused rapid cessation of DNA synthesis and growth arrest.
  • Loss of Cdc7 function induced DNA repair responses (Rad51 foci) and G2/M checkpoint activation.
  • Significant p53 activation and p53-dependent apoptosis were observed, indicating a role in maintaining genetic integrity.

Conclusions:

  • Cdc7 is essential for the continuation of DNA synthesis in mammalian cells.
  • Defective origin activation due to Cdc7 loss generates DNA replication checkpoint signals.
  • Efficient elimination of cells with perturbed replication via apoptosis is crucial for maintaining genetic integrity in stem cells.

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