134 research outputs found
A novel approach for organelle-specific DNA damage targeting reveals different susceptibility of mitochondrial DNA to the anticancer drugs camptothecin and topotecan
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 âpetiteâ cells, respectively. In wild-type cells, toxic topoisomerase IâDNA 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 top1Î 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
Nature des radiolĂ©sions induites dans lâacide dĂ©soxyribonuclĂ©ique et leur rĂ©paration
La nature des diffĂ©rentes lĂ©sions provoquĂ©es par les rayonnements ionisants au niveau de lâADN est dĂ©crite. Il s'agit de lâinduction de ruptures dâun brin ou des deux brins de la chaĂźne dâADN et de modifications des bases. Les principaux processus enzymatiques de rĂ©parations de ces altĂ©rations du matĂ©riel gĂ©nĂ©tique sont rappelĂ©s
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