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Akt/PKB suppresses DNA damage processing and checkpoint activation in late G2

Naihan Xu1, Nadia Hegarat, Elizabeth J Black

  • 1The Beatson Institute for Cancer Research, Glasgow G61 1BD, Scotland, UK.

The Journal of Cell Biology
|August 4, 2010
PubMed

Insights

Late G2 cells fail to repair DNA damage and delay mitosis after irradiation due to inhibited DNA double-strand break processing. Akt inhibition restores this process, highlighting its role in DNA repair and checkpoint activation.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Cell cycle checkpoints are crucial for preventing genomic instability.
  • DNA damage response pathways regulate cell cycle progression.
  • The role of Akt/PKB in DNA damage response is not fully understood.

Purpose of the Study:

  • To investigate the DNA damage response in late G2 phase cells.
  • To identify factors regulating checkpoint activation and DNA repair in late G2.
  • To explore the role of Akt/PKB in this process.

Main Methods:

  • Chemical genetics to inhibit Cyclin-dependent kinase 1 (Cdk1).
  • Irradiation to induce DNA damage.
  • Analysis of DNA damage markers (gamma-H2AX foci).
  • Assessment of checkpoint protein recruitment (RPA, ATR, Rad51, CtIP) and activation (Chk1).
  • Inhibition of Akt/PKB (protein kinase B).

Main Results:

  • Cells arrested in late G2 with Cdk1 inhibition cannot delay mitotic entry after irradiation.
  • Late G2 cells detect DNA damage but fail to activate Chk1 due to impaired DNA double-strand break processing.
  • Essential DNA repair proteins (RPA, ATR, Rad51, CtIP) are not recruited to damage sites.
  • Inhibition of Akt/PKB restores DNA damage processing and Chk1 activation in late G2 cells.

Conclusions:

  • Akt/PKB plays a critical role in regulating DNA repair and checkpoint activation in late G2 phase.
  • Impaired DNA damage processing in late G2 cells is linked to Akt activity.
  • These findings have implications for cancer therapy, particularly in tumors with activated Akt/PKB.

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