This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplemental material
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Shen, C.
Right arrow Articles by Bjornsti, M.-A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Shen, C.
Right arrow Articles by Bjornsti, M.-A.

 Previous Article  |  Next Article 

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{triangledown} ,{dagger}

Changxian Shen, Cynthia S. Lancaster, Bin Shi,{ddagger} 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.

* Corresponding author. Mailing address: Department of Molecular Pharmacology, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105. Phone: (901) 495-2315. Fax: (901) 495-4290. E-mail: mary-ann.bjornsti{at}stjude.org

{triangledown} Published ahead of print on 13 August 2007.

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

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

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.



This article has been cited by other articles:

  • Braunstein, S., Badura, M. L., Xi, Q., Formenti, S. C., Schneider, R. J. (2009). Regulation of Protein Synthesis by Ionizing Radiation. Mol. Cell. Biol. 29: 5645-5656 [Abstract] [Full Text]  
  • Schonbrun, M., Laor, D., Lopez-Maury, L., Bahler, J., Kupiec, M., Weisman, R. (2009). TOR Complex 2 Controls Gene Silencing, Telomere Length Maintenance, and Survival under DNA-Damaging Conditions. Mol. Cell. Biol. 29: 4584-4594 [Abstract] [Full Text]  
  • Barbone, D., Yang, T.-M., Morgan, J. R., Gaudino, G., Broaddus, V. C. (2008). Mammalian Target of Rapamycin Contributes to the Acquired Apoptotic Resistance of Human Mesothelioma Multicellular Spheroids. J. Biol. Chem. 283: 13021-13030 [Abstract] [Full Text]  
  • Houghton, P. J, Easton, J. B, Kurmasheva, R. T (2008). mTOR as a Target for Cancer Therapy. aacredbook 2008: 111-120 [Abstract] [Full Text]  
  • Kanoh, J., Yanagida, M. (2007). Tel2: a common partner of PIK-related kinases and a link between DNA checkpoint and nutritional response?. GENES CELLS 12: 1301-1304 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»