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TORC2 signaling pathway guarantees genome stability in the face of DNA strand breaks

Kenji Shimada1, Ireos Filipuzzi, Michael Stahl

  • 1Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland.

Molecular Cell
|September 17, 2013
PubMed

Insights

A novel inhibitor targeting the target of rapamycin (TOR) pathway was found to cause synthetic lethality in yeast with DNA damage. This lethality is linked to TORC2-mediated actin regulation, impacting DNA repair and survival.

Area of Science:

  • Cell Biology
  • Genetics
  • Biochemistry

Background:

  • Replication stress responses are crucial for maintaining genomic stability.
  • Target of Rapamycin (TOR) signaling pathways regulate cell growth and stress responses.
  • Understanding DNA damage survival mechanisms is vital for cancer research.

Purpose of the Study:

  • To identify novel compounds that sensitize yeast with compromised replication stress response to DNA damaging agents.
  • To elucidate the molecular mechanisms underlying synthetic lethality induced by a TOR inhibitor in combination with DNA damaging agents.
  • To investigate the role of TORC2 and actin cytoskeleton regulation in DNA damage tolerance.

Main Methods:

  • Chemicogenetic screening in budding yeast mutants with impaired replication stress response.
  • Assessing sensitivity to DNA damaging agents (hydroxyurea, camptothecin, Zeocin, ionizing radiation).
  • Genetic manipulation of TOR pathway components (Tor2, Ypk1/Ypk2) and actin cytoskeleton regulators.

Main Results:

  • A TORC1/2 inhibitor was identified that selectively enhances sensitivity to DNA damaging agents in yeast.
  • The inhibitor exhibited synthetic lethality with Zeocin or ionizing radiation, causing rapid chromosome fragmentation.
  • Lethality was dependent on TORC2 inhibition, not TORC1, and linked to Ypk1/Ypk2 activity and actin cytoskeleton integrity.
  • Actin modulators phenocopied TORC2 inhibition effects on DNA damage sensitivity.

Conclusions:

  • TORC2 signaling, through Ypk1/Ypk2 and actin regulation, plays a critical role in yeast survival under DNA damaging conditions.
  • Targeting TORC2 offers a potential strategy for sensitizing cells to DNA damaging therapies.
  • Actin cytoskeleton dynamics are implicated in DNA damage tolerance pathways.

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