Camptothecin resistance is determined by the regulation of topoisomerase I degradation mediated by ubiquitin proteasome pathway

Oncotarget. 2017 Jul 4;8(27):43733-43751. doi: 10.18632/oncotarget.16376.


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.

Keywords: BRCA1; DNAPK; PTEN; topoisomerase I; ubiquitin proteasome pathway.

MeSH terms

  • BRCA1 Protein / metabolism
  • Camptothecin / pharmacology*
  • Cell Line, Tumor
  • DNA Topoisomerases, Type I / metabolism*
  • DNA-Binding Proteins / metabolism
  • Drug Resistance, Neoplasm*
  • Gene Editing
  • Humans
  • Ku Autoantigen / metabolism
  • Multiprotein Complexes / metabolism
  • PTEN Phosphohydrolase / metabolism
  • Phosphorylation
  • Proteasome Endopeptidase Complex / metabolism*
  • Protein Binding
  • Protein Kinase C / metabolism
  • Proteolysis
  • RNA Interference
  • Topoisomerase I Inhibitors / pharmacology*
  • Ubiquitin / metabolism*


  • BRCA1 Protein
  • DNA-Binding Proteins
  • Multiprotein Complexes
  • Topoisomerase I Inhibitors
  • Ubiquitin
  • Protein Kinase C
  • PTEN Phosphohydrolase
  • Proteasome Endopeptidase Complex
  • Ku Autoantigen
  • DNA Topoisomerases, Type I
  • Camptothecin