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ToxSci Advance Access published online on October 5, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfp238
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© The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Rapamycin inhibits yeast nucleotide excision repair independently of Tor kinases

Melvin V. Limson1 and Kevin S. Sweder2,*

1 American Physiological Society, Education Office, 9650 Rockville Pike, Bethesda, MD 20814-3991 2 Bristol-Myers Squibb Company, Research and Development, 6000 Thompson Road, East Syracuse, NY 13057-5050

* Corresponding Author Telephone: (315) 432-2357, Fax: (315) 432-2172, email: kevin.sweder{at}bms.com

Received April 16, 2009; revision received September 2, 2009; accepted September 2, 2009


  Abstract

The yeast target of rapamycin kinases, Tor1 and Tor2, belong to the phosphatidylinositol 3-kinase related family of proteins, which are involved in the cellular response to DNA damage and changes in nutrient conditions. In contrast to yeast, many eukaryotes possess a single Tor kinase. Regardless of the number of Tor kinases in an organism, two distinct complexes involving Tor proteins exist in eukaryotes, TORC1 and TORC2. The yeast TORC1, containing Tor1 or Tor2, is sensitive to the antibiotic rapamycin. The yeast TORC2 is insensitive to rapamycin. We examined the influence of rapamycin treatment upon yeast transcription-coupled nucleotide excision repair in a gene transcribed by RNA polymerase II. We also examined tor mutants for their ability to perform transcription-coupled repair in the absence or presence of rapamycin. Ostensibly lacking TORC1 and TORC2 function, a tor1tor2ts mutant grown at the nonpermissive temperature exhibited similar rates of repair as the wild-type strain. However, repair of both strands in genes decreases in the wild-type strain and the tor1tor2ts mutant exposed to rapamycin. Rapamycin may be inhibiting DNA repair independently of the Tor kinases. In yeast, FPR1 encodes the rapamycin-binding protein Fpr1 that inhibits the TORC1 kinase in the presence of rapamycin. Fap1 competes with rapamycin for Fpr1 binding. Deletion of the FPR1 or FAP1 gene abolishes the inhibitory effect of rapamycin on repair. Thus, the decreased repair observed following rapamycin treatment is independent of TORC1/2 function and likely due to a function of Fap1. We suggest that Fap1 and peptidyl prolyl isomerases, particularly Fpr1, function in the cellular response to genotoxic stress. Our findings have clinical implications for genetic toxicities associated with genotoxic agents when co-administered with rapamycin.

Key Words: Fap1; Fpr1; NER; Tor; transcription-coupled repair.


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