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A role for VCP/p97 in the processing of drug-stabilized TOP2-DNA covalent complexes

Lookup NU author(s): Rebecca Swan, Dr Ian CowellORCiD, Emerita Professor Caroline AustinORCiD

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).

Abstract

Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics. 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 DNA break (DSB) via a 5'-phosphotyro-syl bond. Repair of the enzyme-induced DSB first requires the removal of the TOP2 protein adduct, which, among other mechanisms, can be accomplished through the proteasomal degradation of TOP2. VCP/p97 is a AAA ATPase that utilizes energy from ATP hydrolysis to unfold protein substrates, which can facilitate proteasomal degradation by extracting target proteins from certain cellular structures (such as chromatin) and/or by aiding their translocation into the proteolytic core of the proteasome. In this study, we show that inhibition of VCP/p97 leads to the prolonged accumulation of etoposide-induced TOP2A and TOP2B complexes in a manner that is epistatic with the proteasomal pathway. VCP/p97 inhibition also reduces the etoposide-induced phosphorylation of histone H2A.X, indicative of fewer DSBs. This suggests that VCP/p97 is required for the proteasomal degradation of TOP2-DNA covalent complexes and is thus likely to be an important mediator of DSB repair after treatment with a TOP2 poison. SIGNIFICANCE STATEMENT TOP2 poisons are chemotherapeutic agents used in the treatment of a range of cancers. A better understanding of how TOP2 poison-induced DNA damage is repaired could improve therapy with TOP2 poisons by increasing TOP2 poison cytotoxicity and reducing genotoxicity. The results presented herein suggest that repair of TOP2-DNA covalent complexes involves the protein segregase VCP/p97.

Publication metadata

Author(s): Swan RL, Cowell IG, Austin CA

Publication type: Article

Publication status: Published

Journal: Molecular Pharmacology

Year: 2021

Volume: 100

Issue: 1

Pages: 57-62

Online publication date: 09/07/2021

Acceptance date: 14/04/2021

Date deposited: 08/01/2022

ISSN (print): 0026-895X

ISSN (electronic): 1521-0111

Publisher: American Society for Pharmacology and Experimental Therapy

URL: https://doi.org/10.1124/MOLPHARM.121.000262

DOI: 10.1124/MOLPHARM.121.000262

PubMed id: 33941661

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