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Título

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

AutorDíaz de la Loza, M. Carmen CSIC; Wellinger, Ralf Erik CSIC ORCID
Fecha de publicación2009
EditorOxford University Press
CitaciónNucleic Acids Research 37(4): e26 (2009)
ResumenDNA 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 respirationdeficient ‘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" 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.
Descripción12 páginas, 6 figuras, 1 tabla.-- This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License.
Versión del editorhttp://dx.doi.org/10.1093/nar/gkn1087
URIhttp://hdl.handle.net/10261/38419
DOI10.1093/nar/gkn1087
ISSN0305-1048
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