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ToxSci Advance Access published online on November 1, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfp267
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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

Creation of a Hyper-permeable Yeast Strain to Genotoxic Agents through Combined Inactivation of PDR and CWP Genes

Min Zhang1, Michelle Hanna2, Jia Li2, Susan Butcher2, Heping Dai1,* and Wei Xiao2,*

1 Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei, 430072 China 2 Department of Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK S7N 5E5 Canada

* To whom correspondence should be addressed at Institute of Hydrobiology, Chinese Academy of Sciences, 7 Donghu Road South, Wuhan, Hubei, 430072 China. Fax: 86-27-68780123. E-mail: hpdai{at}ihb.ac.cn (H.D.) or Department of Microbiology and Immunology, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK S7N 5E5 Canada. Fax: 306-966-4298. E-mail: wei.xiao{at}usask.ca (W.X.)

Received August 3, 2009; revision received October 9, 2009; accepted October 22, 2009


  Abstract

We previously established a genotoxicity detection system based on the transcriptional response of the yeast RNR3 gene to DNA damage. In order to further improve its sensitivity to genotoxicants, we have attempted to increase cell permeability by removing cell wall mannoproteins (CWPs). Here, we report that selected deletion of pleiotropic drug resistance (PDR) genes encoding membrane efflux transporters also enhanced cellular sensitivity to treatment by various genotoxic agents. Furthermore, we have validated our hypothesis that PDR and CWP protect cells through different mechanisms by demonstrating that simultaneous inactivation of the above two pathways resulted in a synergistic enhancement of assay sensitivity as measured by RNR3-lacZ expression, and that this effect is at the cell permeability level. The quadruple mutation results in RNR3-lacZ assay sensitivity to tested chemicals that apparently surpasses the industry standard Ames test. We argue that this hyper-permeable yeast mutant strain would be suitable for other chemical-based genotoxic assays.

Key Words: Saccharomyces cerevisiae; RNR3-lacZ; genotoxicity test; permeability; ABC transporters; cell wall.


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