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Nucleic Acids Research Advance Access published online on January 16, 2009
Nucleic Acids Research, doi:10.1093/nar/gkn1087
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© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Methods Online

A novel approach for organelle-specific DNA damage targeting reveals different susceptibility of mitochondrial DNA to the anticancer drugs camptothecin and topotecan

M. C. Díaz de la Loza and R. E. Wellinger*

Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Universidad de Sevilla – CSIC, Avda, Américo Vespucio s/n, 41092 - Sevilla, Spain

*To whom correspondence should be addressed. Tel: +34 954 468 004; Fax: +34 954 461 664; Email: ralf.wellinger{at}cabimer.es

Received July 17, 2008. Revised December 25, 2008. Accepted December 29, 2008.

DNA is susceptible of being damaged by chemicals, UV light or gamma irradiation. Nuclear DNA damage invokes both a checkpoint and a repair response. By contrast, little is known about the cellular response to mitochondrial DNA damage. We designed an experimental system that allows organelle-specific DNA damage targeting in Saccharomyces cerevisiae. DNA damage is mediated by a toxic topoisomerase I allele which leads to the formation of persistent DNA single-strand breaks. We show that organelle-specific targeting of a toxic topoisomerase I to either the nucleus or mitochondria leads to nuclear DNA damage and cell death or to loss of mitochondrial DNA and formation of respiration-deficient ‘petite’ cells, respectively. In wild-type cells, toxic topoisomerase I–DNA intermediates are formed as a consequence of topoisomerase I interaction with camptothecin-based anticancer drugs. We reasoned that targeting of topoisomerase I to the mitochondria of top1{Delta} cells should lead to petite formation in the presence of camptothecin. Interestingly, camptothecin failed to generate petite; however, its derivative topotecan accumulates in mitochondria and induces petite formation. Our findings demonstrate that drug modifications can lead to organelle-specific DNA damage and thus opens new perspectives on the role of mitochondrial DNA-damage in cancer treatment.


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I. D. Rosa, S. Goffart, M. Wurm, C. Wiek, F. Essmann, S. Sobek, P. Schroeder, H. Zhang, J. Krutmann, H. Hanenberg, et al.
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