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Apoptotic Topoisomerase I-DNA Complexes Induced by Staurosporine-mediated Oxygen Radicals

Abstract : Topoisomerase I (Top1), an abundant nuclear enzyme expressed throughout the cell cycle, relaxes DNA supercoiling by forming transient covalent DNA cleavage complexes. We show here that staurosporine, a ubiquitous inducer of apoptosis in mammalian cells, stabilizes cellular Top1 cleavage complexes. These complexes are formed indirectly as staurosporine cannot induce Top1 cleavage complexes in normal DNA with recombinant Top1 or nuclear extract from normal cells. In treated cells, staurosporine produces oxidative DNA lesions and generates reactive oxygen species (ROS). Quenching of these ROS by the antioxidant N-acetyl-l-cysteine or inhibition of the mitochondrial dependent production of ROS by the caspase inhibitor benzyloxycarbonyl-VAD prevents staurosporine-induced Top1 cleavage complexes. Down-regulation of Top1 by small interfering RNA decreases staurosporine-induced apoptotic DNA fragmentation. We propose that Top1 cleavage complexes resulting from oxidative DNA lesions generated by ROS in staurosporine-treated cells contribute to the full apoptotic response.
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https://www.hal.inserm.fr/inserm-02438646
Contributor : Philippe Pourquier <>
Submitted on : Tuesday, January 14, 2020 - 12:09:46 PM
Last modification on : Thursday, July 2, 2020 - 5:40:11 PM

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Olivier Sordet, Qasim Khan, Isabelle Plo, Philippe Pourquier, Yoshimasa Urasaki, et al.. Apoptotic Topoisomerase I-DNA Complexes Induced by Staurosporine-mediated Oxygen Radicals. Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2004, 279 (48), pp.50499-50504. ⟨10.1074/jbc.M410277200⟩. ⟨inserm-02438646⟩

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