26 S proteasome-mediated degradation of topoisomerase II cleavable complexes
26 S proteasome-mediated degradation of topoisomerase II cleavable complexes
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DOI：
10.1074/jbc.m104009200
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发表时间：
2001-11-02
影响因子：
4.8
通讯作者：
Liu, LF
中科院分区：
文献类型：
--
作者：
Mao, Y;Desai, SD;Liu, LF
DNA 拓扑异构酶 II (TOP2) 可切割复合物代表了一种不寻常的 DNA 损伤类型，其特征是可逆的 TOP2-DNA 交联和 DNA 双链断裂。已知许多抗肿瘤药物和生理应激会诱导 TOP2 可裂解复合物，导致细胞凋亡和基因组不稳定。然而，修复 TOP2 可裂解复合物的分子机制仍不清楚。在目前的研究中，我们表明由原型 TOP2 毒物 VM-26 诱导的 TOP2 可裂解复合物可通过泛素/26 S 蛋白酶体途径进行蛋白水解降解。令人惊讶的是，TOP2 β 同工酶比 TOP2 α 同工酶优先被降解。此外，转录抑制剂如5,6-二氯苯并咪唑核苷和喜树碱可以显着阻断VM-26诱导的TOP2β降解。这些结果与 TOP2 β 可裂解复合物的修复可能涉及 TOP2 β 的转录依赖性蛋白水解以揭示蛋白质隐藏的双链断裂的模型一致。
DNA topoisomerase II (TOP2) cleavable complexes represent an unusual type of DNA damage characterized by reversible TOP2-DNA cross-links and DNA double strand breaks. Many antitumor drugs and physiological stresses are known to induce TOP2 cleavable complexes leading to apoptotic cell death and genomic instability. However, the molecular mechanism(s) for repair of TOP2 cleavable complexes remains unclear. In the current studies, we show that TOP2 cleavable complexes induced by the prototypic TOP2 poison VM-26 are proteolytically degraded by the ubiquitin/26 S proteasome pathway. Surprisingly the TOP2 beta isozyme is preferentially degraded over TOP2 alpha isozyme. In addition, transcription inhibitors such as 5,6-dichlorobenzimidazole riboside and camptothecin can substantially block VM-26-induced TOP2 beta degradation. These results are consistent with a model in which the repair of TOP2 beta cleavable complexes may involve transcription-dependent proteolysis of TOP2 beta to reveal the protein-concealed double strand breaks.