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Small Molecule Inhibitors Confirm Ubiquitin-Dependent Removal of TOP2-DNA Covalent Complexes.
Molecular Pharmacology ( IF 3.2 ) Pub Date : 2020-09-01 , DOI: 10.1124/mol.119.118893 Rebecca L Swan 1 , Luke L K Poh 1 , Ian G Cowell 2 , Caroline A Austin 2
Molecular Pharmacology ( IF 3.2 ) Pub Date : 2020-09-01 , DOI: 10.1124/mol.119.118893 Rebecca L Swan 1 , Luke L K Poh 1 , Ian G Cowell 2 , Caroline A Austin 2
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DNA topoisomerase II (TOP2) is required for the unwinding and decatenation of DNA through the induction of an enzyme-linked double-strand break (DSB) in one DNA molecule and passage of another intact DNA duplex through the break. Anticancer drugs targeting TOP2 (TOP2 poisons) prevent religation of the DSB and stabilize a normally transient intermediate of the TOP2 reaction mechanism called the TOP2-DNA covalent complex. Subsequently, TOP2 remains covalently bound to each end of the enzyme-bridged DSB, which cannot be repaired until TOP2 is removed from the DNA. One removal mechanism involves the proteasomal degradation of the TOP2 protein, leading to the liberation of a protein-free DSB. Proteasomal degradation is often regulated by protein ubiquitination, and here we show that inhibition of ubiquitin-activating enzymes reduces the processing of TOP2A- and TOP2B-DNA complexes. Depletion or inhibition of ubiquitin-activating enzymes indicated that ubiquitination was required for the liberation of etoposide-induced protein-free DSBs and is therefore an important layer of regulation in the repair of TOP2 poison–induced DNA damage. TOP2-DNA complexes stabilized by etoposide were shown to be conjugated to ubiquitin, and this was reduced by inhibition or depletion of ubiquitin-activating enzymes.
中文翻译：
小分子抑制剂证实了 TOP2-DNA 共价复合物的泛素依赖性去除。
DNA 拓扑异构酶 II (TOP2) 是 DNA 解旋和串联所必需的，通过在一个 DNA 分子中诱导酶联双链断裂 (DSB) 并通过断裂使另一个完整的 DNA 双链体通过。靶向 TOP2 的抗癌药物（TOP2 毒物）可防止 DSB 重新连接，并稳定 TOP2 反应机制中通常短暂的中间体（称为 TOP2-DNA 共价复合物）。随后，TOP2 仍与酶桥 DSB 的两端共价结合，直到从 DNA 中去除 TOP2 后，DSB 才能被修复。一种去除机制涉及 TOP2 蛋白的蛋白酶体降解，导致释放无蛋白的 DSB。蛋白酶体降解通常受到蛋白质泛素化的调节，在这里我们表明，抑制泛素激活酶会减少 TOP2A-和 TOP2B-DNA 复合物的加工。泛素激活酶的耗尽或抑制表明，泛素化是释放依托泊苷诱导的无蛋白质 DSB 所必需的，因此是修复 TOP2 毒物诱导的 DNA 损伤的重要调节层。通过依托泊苷稳定的 TOP2-DNA 复合物显示出与泛素缀合，并且通过抑制或耗尽泛素激活酶可以减少这种情况。
更新日期：2020-08-20
中文翻译：
小分子抑制剂证实了 TOP2-DNA 共价复合物的泛素依赖性去除。
DNA 拓扑异构酶 II (TOP2) 是 DNA 解旋和串联所必需的，通过在一个 DNA 分子中诱导酶联双链断裂 (DSB) 并通过断裂使另一个完整的 DNA 双链体通过。靶向 TOP2 的抗癌药物（TOP2 毒物）可防止 DSB 重新连接，并稳定 TOP2 反应机制中通常短暂的中间体（称为 TOP2-DNA 共价复合物）。随后，TOP2 仍与酶桥 DSB 的两端共价结合，直到从 DNA 中去除 TOP2 后，DSB 才能被修复。一种去除机制涉及 TOP2 蛋白的蛋白酶体降解，导致释放无蛋白的 DSB。蛋白酶体降解通常受到蛋白质泛素化的调节，在这里我们表明，抑制泛素激活酶会减少 TOP2A-和 TOP2B-DNA 复合物的加工。泛素激活酶的耗尽或抑制表明，泛素化是释放依托泊苷诱导的无蛋白质 DSB 所必需的，因此是修复 TOP2 毒物诱导的 DNA 损伤的重要调节层。通过依托泊苷稳定的 TOP2-DNA 复合物显示出与泛素缀合，并且通过抑制或耗尽泛素激活酶可以减少这种情况。
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