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

Ando K, Shah AK, Sachdev V, Kleinstiver BP, Taylor-Parker J, Welch MM, Hu Y, Salgia R, White FM, Parvin JD, Ozonoff A, Rameh LE, Joung JK, Bharti AK
Oncotarget. 2017 8 (27): 43733-43751

PMID: 28415827 · PMCID: PMC5546437 · 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.

MeSH Terms (19)

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

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