拓扑异构酶
蛋白酶体
DNA损伤
基因组不稳定性
DNA
细胞生物学
生物
DNA修复
蛋白质水解
依托泊苷
劈理(地质)
分子生物学
化学
生物化学
酶
遗传学
古生物学
化疗
断裂(地质)
作者
Nicholas Sciascia,Wei Wu,Dali Zong,Yilun Sun,Nancy Wong,Sam John,Darawalee Wangsa,Thomas Ried,Samuel F. Bunting,Yves Pommier,André Nussenzweig
出处
期刊:eLife
[eLife Sciences Publications, Ltd.]
日期:2020-02-14
卷期号:9
被引量:27
摘要
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.
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