SCF?-TrCP-mediated degradation of TOP2? promotes cancer cell survival in response to chemotherapeutic drugs targeting topoisomerase II.

ABSTRACT: Topoisomerase II (TOP2)-targeting anticancer chemotherapeutic drugs, termed TOP2 poisons, are widely used and effective in the clinic by stabilizing TOP2-DNA covalent complexes to induce DNA double-strand breaks (DSBs) and ultimately, cause cell death. The stabilized TOP2-DNA complex is known to be degraded by proteasome, whereas the underlying mechanism for instant TOP2? degradation in response to TOP2 poisons and the subsequent biological consequence remain elusive. Here, we reported that TOP2 poison-induced TOP2? degradation is mediated by SCF?-TrCP ubiquitin ligase. Specifically, DNA damage signal, triggered by teniposide (VM-26) treatment, activates ATM, cooperating with CK1 to phosphorylate TOP2? on Ser1134 and Ser1130, respectively, in a canonical degron motif to facilitate ?-TrCP binding and subsequent degradation. Inactivation of ATM, CK1 or SCF?-TrCP by small molecular inhibitors or genetic knockdown/knockout abrogates TOP2? degradation. Biologically, blockage of TOP2? degradation in combination with VM-26 treatment impairs DNA damage response and repair, leading to an accelerated cell death via apoptosis. Thus, it appears that TOP2? degradation is a cellular defensive mechanism to facilitate the exposure of DSBs to trigger DNA damage response and repair. Collectively, our findings reveal a new strategy to improve the efficacy of TOP2 poisons in combination with small-molecule inhibitors against TOP2? degradation.

SUBMITTER: Shu J 

PROVIDER: S-EPMC6997367 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature