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TOR signaling is a determinant of cell survival in response to DNA damage

Changxian Shen1, Cynthia S Lancaster, Bin Shi

  • 1Department of Molecular Pharmacology, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105, USA.

Molecular and Cellular Biology
|August 19, 2007
PubMed

Insights

Target of rapamycin (TOR) kinase regulates cell survival during genotoxic stress. Inhibiting TORC1 signaling in yeast enhances lethality from DNA damage by blocking DNA repair, impacting cancer drug resistance.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Genetics

Background:

  • The conserved target of rapamycin (TOR) kinase pathway, particularly TORC1, is crucial for cellular responses to environmental stressors like starvation and hypoxia.
  • Dysregulation of Akt-TOR signaling is implicated in cancer development, making this pathway a target for chemotherapeutics.

Purpose of the Study:

  • To investigate the role of rapamycin-sensitive TORC1 signaling in yeast cell survival and S-phase progression under genotoxic stress.
  • To elucidate the mechanism by which TORC1 influences DNA damage response and mutagenesis.

Main Methods:

  • Utilized yeast models exposed to the DNA-damaging agent methyl methanesulfonate (MMS).
  • Assessed the impact of rapamycin inhibition on TORC1 signaling, S-phase checkpoint activation (Rad53), and ribonucleotide reductase (Rnr1, Rnr3) expression.
  • Examined cell viability and mutagenesis rates in wild-type and RNR3-deleted yeast strains.

Main Results:

  • Rapamycin-sensitive TORC1 signaling is essential for yeast cell viability and S-phase progression following genotoxic stress.
  • TORC1 inhibition suppressed Rad53-mediated induction of Rnr1 and Rnr3, reducing MMS-induced mutagenesis but increasing cell lethality.
  • Deletion of RNR3 conferred hypersensitivity to combined rapamycin and MMS treatment, highlighting Rnr3's role in DNA damage survival.

Conclusions:

  • TORC1 functions as a survival pathway during genotoxic stress by maintaining deoxynucleoside triphosphate pools for DNA repair polymerases.
  • TOR-dependent survival under DNA-damaging conditions correlates with increased mutation rates, potentially contributing to chemotherapeutic resistance.

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