title: A novel approach for organelle-specific DNA damage targeting reveals different susceptibility of mitochondrial DNA to the anticancer drugs camptothecin and topotecan.
abstract: 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.
authors.affiliation: Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Universidad de Sevilla - CSIC, Avda, Américo Vespucio s/n, 41092, Sevilla, Spain.
authors.forename: M C Díaz
authors.initials: MC
authors.lastname: de la Loza
authors.forename: R E
authors.initials: RE
authors.lastname: Wellinger
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism / Q000633:toxicity*; D002166:Camptothecin / Q000633:toxicity*; D002467:Cell Nucleus / Q000201:enzymology; D004249:DNA Damage; D004264:DNA Topoisomerases, Type I / Q000235:genetics / Q000378:metabolism*; D004272:DNA, Mitochondrial / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D019772:Topotecan / Q000378:metabolism / Q000633:toxicity*
chemical_list: D000970:Antineoplastic Agents; D004272:DNA, Mitochondrial; D019772:Topotecan; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin