Camptothecin resistance is determined by the regulation of topoisomerase I degradation mediated by ubiquitin proteasome pathway
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Koji Ando1,*, Ankur K. Shah1,*, Vibhu Sachdev1, Benjamin P. Kleinstiver2,3, Julian Taylor-Parker1, Moira M. Welch2, Yiheng Hu4, Ravi Salgia5, Forest M. White6, Jeffrey D. Parvin4, Al Ozonoff7, Lucia E. Rameh8 , J. Keith Joung2,3 and Ajit K. Bharti1
1 Department of Medicine, Division of Hematology Oncology, Boston University School of Medicine, Boston, MA, USA
2 Molecular Pathology Unit, Massachusetts General Hospital, Charlestown, MA, USA
3 Department of Pathology, Harvard Medical School, Boston, MA, USA
4 Department of Biomedical Informatics, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
5 Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte , CA, USA
6 Department of Biological Engineering, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
7 Center for Patient Safety and Quality Research, Boston Children’s Hospital, Boston, MA, USA
8 Department of Medicine, Obesity Research Center, Boston University School of Medicine, Boston, MA, USA
* These authors have contributed equally to this work
Ajit K Bharti, email:
Keywords: topoisomerase I, BRCA1, DNAPK, PTEN, ubiquitin proteasome pathway
Received: February 17, 2017 Accepted: March 03, 2017 Published: March 18, 2017
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.
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