Suppressing proteasome mediated processing of topoisomerase II DNA-protein complexes preserves genome integrity
Abstract
Topoisomerase II (TOP2) relieves topological stress in DNA by introducing double-strand breaks (DSBs) via a transient, covalently linked TOP2 DNA-protein intermediate, termed TOP2 cleavage complex (TOP2cc). TOP2ccs are normally rapidly reversible, but can be stabilized by TOP2 poisons, such as the chemotherapeutic agent etoposide (ETO). TOP2 poisons have shown significant variability in their therapeutic effectiveness across different cancers for reasons that remain to be determined. One potential explanation for the differential cellular response to these drugs is in the manner by which cells process TOP2ccs. Cells are thought to remove TOP2ccs primarily by proteolytic degradation followed by DNA DSB repair. Here, we show that proteasome-mediated repair of TOP2cc is highly error-prone. Pre-treating primary splenic mouse B-cells with proteasome inhibitors prevented the proteolytic processing of trapped TOP2ccs, suppressed the DNA damage response (DDR) and completely protected cells from ETO-induced genome instability, thereby preserving cellular viability. When degradation of TOP2cc was suppressed, the TOP2 enzyme uncoupled itself from the DNA following ETO washout, in an error-free manner. This suggests a potential mechanism of developing resistance to topoisomerase poisons by ensuring rapid TOP2cc reversal.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Feb 14, 2020
- Source ID
- 10.7554/elife.53447
Entities
People
- Andre Nussenzweig
- Dali Zong
- Darawalee Wangsa
- Nancy Wong
- Nicholas Sciascia
- Sam John
- Samuel F Bunting
- Thomas Ried
- Wei Wu
- Yilun Sun
- Yves Pommier
Organizations
- Alex's Lemonade Stand Foundation
- Ellison Medical Foundation
- George Washington University
- National Cancer Institute
- National Institutes of Health
- Rutgers University
- United States Department of Defense