SCFβ-TrCP-mediated degradation of TOP2β 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 TOP2β degradation in response to TOP2 poisons and the subsequent biological consequence remain elusive. Here, we reported that TOP2 poison-induced TOP2β degradation is mediated by SCF β-TrCP ubiquitin ligase. Specifically, DNA damage signal, triggered by teniposide (VM-26) treatment, activates ATM, cooperating with CK1 to phosphorylate TOP2β on Ser1134 and Ser1130, respectively, in a canonical degron motif to facilitate β-TrCP binding and subsequent degradation. Inactivation of ATM, CK1 or SCF β-TrCP by small molecular inhibitors or genetic knockdown/knockout abrogates TOP2β degradation. Biologically, blockage of TOP2β 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 TOP2β 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 TOP2β degradation.

Recent advances and future directions in anti‐tumor activity of cryptotanshinone: A mechanistic review

“…There are two characteristic types of topos including DNA topoisomerase 1 (topo1) and DNA topoisomerase 2 (topo2) that have been shown to regulate chromosomal segregation and DNA replication, recombination and repair (Alvarez‐Quilon et al, 2020; Singh, Luxami, & Paul, 2020). Consequently, much attention has been directed towards targeting topos in cancer therapy to suppress growth and proliferation of cancer cells (Shu et al, 2020; Watanabe et al, 2020). It is said that CT is a naturally occurring inhibitor of topo2 that is able to remarkably inhibit proliferation and invasion of lung cancer cells.…”

Thermodynamic Dissection of the Intercalation Binding Process of Doxorubicin to dsDNA with Implications of Ionic and Solvent Effects

“…Doxorubicin (trade name Adriamycin, abbreviated DOX) is an intercalator cancer drug that has been widely applied in clinical settings of chemotherapy. − DOX belongs to the anthracycline anticancer group, effective in killing cancer cells in both solid and liquid tumors. − It has three functional domains, as shown in Figure : the anthraquinone ring that intercalates between two BPs of dsDNA, a subsection in the anthraquinone ring that stabilizes the DOX–DNA complex by forming hydrogen bonds (HBs) with DNA bases, and the daunosamine domain with an amino sugar group, which acts as a minor groove binding agent . The intercalation of DOX into DNA deforms the polynucleotide structure, resulting in an inhibition of the macromolecular biosynthesis, due to its interference with the enzyme topoisomerase II, and generation of enzyme-mediated DNA. − Despite the considerable success of DOX in clinical applications as a chemotherapeutic anticancer agent, the underlying modus operandi is still not entirely clear and remains a subject of intense debate. Hence, a detailed analysis of the DOX–DNA interactions can provide in-depth knowledge of the molecular mechanism of intercalator drug action, as well as better understanding of the general principles for guiding the new DNA-intercalator design.…”

Targeting DNA-Protein Crosslinks via Post-Translational Modifications

“…Another ubiquitin ligase BRCA1 has been shown to contribute to the degradation of TOP1-DPCs encountered by transcription machinery (Sordet et al, 2008). Similarly, the ubiquitylation-mediated degradation of etoposide-induced TOP2-DPCs were shown to be dependent on BMI1/RING1A and SCFβ-TrCP ubiquitin E3 ligase complexes (Alchanati et al, 2009;Shu et al, 2020). However, these findings have so far not been further validated and it remains unclear whether these ubiquitin ligases directly target TOP1/2-DPCs.…”