A Role for VCP/p97 in the Processing of Drug-Stabilized TOP2-DNA Covalent Complexes

DNA topoisomerase II (TOP2) poisons induce protein-DNA crosslinks termed TOP2-DNA covalent complexes, in which TOP2 remains covalently bound to each end of an enzyme-induced double-strand break (DSB) via a 5?-phosphotyrosyl bond. Repair the DSB first requires removal protein adduct, which, among other mechanisms, can be accomplished through proteasomal degradation TOP2. VCP/p97 is AAA ATPase that utilizes energy from ATP hydrolysis unfold substrates, facilitate by extracting target proteins certain cellular structures (such as chromatin) and/or aiding their translocation into proteolytic core proteasome. In this study, we show inhibition leads prolonged accumulation etoposide-induced TOP2A and TOP2B complexes manner epistatic with pathway. also reduces phosphorylation histone H2A.X, indicative fewer DSBs. This suggests required for thus likely important mediator repair after treatment poison. SIGNIFICANCE STATEMENT are chemotherapeutic agents used range cancers. A better understanding how poison–induced damage repaired could improve therapy increasing poison cytotoxicity reducing genotoxicity. The results presented herein suggest involves segregase VCP/p97.