Camptothecin resistance is determined by the regulation of topoisomerase I degradation mediated by ubiquitin proteasome pathway.
Camptothecin resistance is determined by the regulation of topoisomerase I degradation mediated by ubiquitin proteasome pathway.
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DOI：
10.18632/oncotarget.16376
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发表时间：
2017-07-04
期刊：
影响因子：
--
通讯作者：
Bharti AK
中科院分区：
文献类型：
--
作者：
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
拓扑异构酶I的蛋白酶体降解是喜树碱(CPT)作用下观察到的最显著的细胞现象之一。重要的是，TOPOI的降解率与CPT抗性有关。Topoi-DNA-CPT可切割复合体的形成抑制了DNA的重新连接，导致DNA双链断裂(DSB)。Topoi的降解标志着泛素蛋白酶体途径(UPP)依赖的DNA损伤反应(DDR)的第一步。在这里，我们证明了Ku70/Ku80异源二聚体与Topoi结合，DNA依赖的蛋白激酶(DNA-PKcs)在丝氨酸10(topoi-PS10)上磷酸化Topo1，后者随后被BRCA1泛素化。较高的TOPOI-PS10基础水平确保了TOPOI的快速降解，从而产生对CPT的抗性。重要的是，PTEN调节该通路中DNA-PKcs的活性，PTEN的缺失确保DNA-PKcs依赖更高的Topoi-PS10、迅速的Topoi降解和对CPT的抗性。
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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