SCFß-TrCP-mediated degradation of TOP2ß 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 TOP2ß degradation in response to TOP2 poisons and the subsequent biological consequence remain elusive. Here, we reported that TOP2 poison-induced TOP2ß degradation is mediated by SCFß-TrCP ubiquitin ligase. Specifically, DNA damage signal, triggered by teniposide (VM-26) treatment, activates ATM, cooperating with CK1 to phosphorylate TOP2ß on Ser1134 and Ser1130, respectively, in a canonical degron motif to facilitate ß-TrCP binding and subsequent degradation. Inactivation of ATM, CK1 or SCFß-TrCP by small molecular inhibitors or genetic knockdown/knockout abrogates TOP2ß degradation. Biologically, blockage of TOP2ß 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 TOP2ß 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 TOP2ß degradation.