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Molecular and Cellular Biology, October 2007, p. 7007-7017, Vol. 27, No. 20
0270-7306/07/$08.00+0     doi:10.1128/MCB.00290-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

TOR Signaling Is a Determinant of Cell Survival in Response to DNA Damage ^,

Changxian Shen, Cynthia S. Lancaster, Bin Shi, Hong Guo, Padma Thimmaiah, and Mary-Ann Bjornsti^*

Department of Molecular Pharmacology, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, Tennessee 38105

Received 16 February 2007/ Returned for modification 1 April 2007/ Accepted 31 July 2007

The conserved TOR (target of rapamycin) kinase is part of a TORC1 complex that regulates cellular responses to environmental stress, such as amino acid starvation and hypoxia. Dysregulation of Akt-TOR signaling has also been linked to the genesis of cancer, and thus, this pathway presents potential targets for cancer chemotherapeutics. Here we report that rapamycin-sensitive TORC1 signaling is required for the S-phase progression and viability of yeast cells in response to genotoxic stress. In the presence of the DNA-damaging agent methyl methanesulfonate (MMS), TOR-dependent cell survival required a functional S-phase checkpoint. Rapamycin inhibition of TORC1 signaling suppressed the Rad53 checkpoint-mediated induction of ribonucleotide reductase subunits Rnr1 and Rnr3, thereby abrogating MMS-induced mutagenesis and enhancing cell lethality. Moreover, cells deleted for RNR3 were hypersensitive to rapamycin plus MMS, providing the first demonstration that Rnr3 contributes to the survival of cells exposed to DNA damage. Our findings support a model whereby TORC1 acts as a survival pathway in response to genotoxic stress by maintaining the deoxynucleoside triphosphate pools necessary for error-prone translesion DNA polymerases. Thus, TOR-dependent cell survival in response to DNA-damaging agents coincides with increased mutation rates, which may contribute to the acquisition of chemotherapeutic drug resistance.

Published ahead of print on 13 August 2007.

Supplemental material for this article may be found at http://mcb.asm.org/.

Present address: Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030.

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