Ando, KojiShah, Ankur K.Sachdev, VibhuKleinstiver, BenjaminTaylor-Parker, JulianWelch, Moira M.Hu, YihengSalgia, RaviWhite, Forest M.Parvin, Jeffrey D.Ozonoff, AlRameh, Lucia E.Joung, J. KeithBharti, Ajit K.2017-11-212017Ando, K., A. K. Shah, V. Sachdev, B. P. Kleinstiver, J. Taylor-Parker, M. M. Welch, Y. Hu, et al. 2017. “Camptothecin resistance is determined by the regulation of topoisomerase I degradation mediated by ubiquitin proteasome pathway.” Oncotarget 8 (27): 43733-43751. doi:10.18632/oncotarget.16376. http://dx.doi.org/10.18632/oncotarget.16376.http://nrs.harvard.edu/urn-3:HUL.InstRepos:34375118Proteasomal 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.en-UStopoisomerase IBRCA1DNAPKPTENubiquitin proteasome pathwayJournal Article2017-11-2110.18632/oncotarget.16376