Camptothecin resistance is determined by the regulation of topoisomerase I degradation mediated by ubiquitin proteasome pathway.
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.
Mesh Terms:
BRCA1 Protein, Camptothecin, Cell Line, Tumor, DNA Topoisomerases, Type I, DNA-Binding Proteins, Drug Resistance, Neoplasm, Gene Editing, Humans, Ku Autoantigen, Multiprotein Complexes, PTEN Phosphohydrolase, Phosphorylation, Proteasome Endopeptidase Complex, Protein Binding, Protein Kinase C, Proteolysis, RNA Interference, Topoisomerase I Inhibitors, Ubiquitin
BRCA1 Protein, Camptothecin, Cell Line, Tumor, DNA Topoisomerases, Type I, DNA-Binding Proteins, Drug Resistance, Neoplasm, Gene Editing, Humans, Ku Autoantigen, Multiprotein Complexes, PTEN Phosphohydrolase, Phosphorylation, Proteasome Endopeptidase Complex, Protein Binding, Protein Kinase C, Proteolysis, RNA Interference, Topoisomerase I Inhibitors, Ubiquitin
Oncotarget
Date: Jul. 04, 2017
PubMed ID: 28415827
View in: Pubmed Google Scholar
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