SUMO-Targeted DNA Translocase Rrp2 Protects the Genome from Top2-Induced DNA Damage
SUMO-Targeted DNA Translocase Rrp2 Protects the Genome from Top2-Induced DNA Damage
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SUMO 靶向 DNA 易位酶 Rrp2 保护基因组免受 Top2 诱导的 DNA 损伤
DOI：
10.1016/j.molcel.2017.04.017
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Du Li-Lin
中科院分区：
文献类型：
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作者：
Wei Yi;Diao Li-Xue;Lu Shan;Wang Hai-Tao;Suo Fang;Dong Meng-Qiu;Du Li-Lin
DNA拓扑异构酶II（Top2）的作用产生通常隐藏在Top2-DNA共价复合物内的瞬时DNA断裂。Top2毒物，包括普遍存在的天然化合物和临床使用的抗癌药物，捕获Top2-DNA复合物。在这里，我们表明细胞积极地阻止Top2降解，以避免隐藏的DNA断裂的暴露。全基因组筛选显示，缺乏Rrp 2（一种Snf 2家族DNA移位酶）的裂殖酵母细胞对Top2毒物非常敏感。Rrp 2的缺失增强了Top2的SUMO化依赖性泛素化和降解，这反过来又增加了Top2-DNA复合物被捕获的位点处的DNA损伤。Rrp 2具有SUMO结合能力，并通过与SUMO靶向泛素连接酶（STUbL）竞争SUMO链结合和从DNA中置换SUMO化的Top2来防止Top2过度降解。Rrp 2的芽殖酵母同源物Uls 1起着类似的作用，表明这种基因组保护机制被广泛采用，这一发现对癌症治疗有意义。
The action of DNA topoisomerase II (Top2) creates transient DNA breaks that are normally concealed inside Top2-DNA covalent complexes. Top2 poisons, including ubiquitously present natural compounds and clinically used anti-cancer drugs, trap Top2-DNA complexes. Here, we show that cells actively prevent Top2 degradation to avoid the exposure of concealed DNA breaks. A genome-wide screen revealed that fission yeast cells lacking Rrp2, an Snf2-family DNA translocase, are strongly sensitive to Top2 poisons. Loss of Rrp2 enhances SUMOylation-dependent ubiquitination and degradation of Top2, which in turn increases DNA damage at sites where Top2-DNA complexes are trapped. Rrp2 possesses SUMO-binding ability and prevents excessive Top2 degradation by competing against the SUMO-targeted ubiquitin ligase (STUbL) for SUMO chain binding and by displacing SUMOylated Top2 from DNA. The budding yeast homolog of Rrp2, Uls1, plays a similar role, indicating that this genome protection mechanism is widely employed, a finding with implications for cancer treatment.