Camptothecin resistance is determined by the regulation of topoisomerase I degradation mediated by ubiquitin proteasome pathway
Author(s)Ando, Koji; Shah, Ankur K.; Sachdev, Vibhu; Kleinstiver, Benjamin P.; Taylor-Parker, Julian; Welch, Moira M.; Hu, Yiheng; Salgia, Ravi; Parvin, Jeffrey D.; Ozonoff, Al; Rameh, Lucia E.; Joung, J. Keith; Bharti, Ajit K.; White, Forest M; ... Show more Show less
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Proteasomal degradation of topoisomerase I (topoI) is one of the most remarkable cellular phenomena observed in response to camptothecin (CPT). Importantly, the rate of topoI degradation is linked to CPT resistance. Formation of the topoI-DNA-CPT cleavable complex inhibits DNA re-ligation resulting in DNA-double strand break (DSB). The degradation of topoI marks the first step in the ubiquitin proteasome pathway (UPP) dependent DNA damage response (DDR). Here, we show that the Ku70/Ku80 heterodimer binds with topoI, and that the DNA-dependent protein kinase (DNA-PKcs) phosphorylates topoI on serine 10 (topoI-pS10), which is subsequently ubiquitinated by BRCA1. A higher basal level of topoI-pS10 ensures rapid topoI degradation leading to CPT resistance. Importantly, PTEN regulates DNA-PKcs kinase activity in this pathway and PTEN deletion ensures DNA-PKcs dependent higher topoI-pS10, rapid topoI degradation and CPT resistance.
DepartmentDavid H. Koch Institute for Integrative Cancer Research at MIT; Massachusetts Institute of Technology. Department of Biological Engineering
Impact Journals/National Center for Biotechnology Information (U.S.)
Ando, Koji; Shah, Ankur K.; Sachdev, Vibhu; Kleinstiver, Benjamin P.; Taylor-Parker, Julian; Welch, Moira M.; Hu, Yiheng et al. “Camptothecin Resistance Is Determined by the Regulation of Topoisomerase I Degradation Mediated by Ubiquitin Proteasome Pathway.” Oncotarget (November 2015): 16376
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