A Synthetic Lethal Interaction between APC/C and Topoisomerase Poisons Uncovered by Proteomic Screens
A Synthetic Lethal Interaction between APC/C and Topoisomerase Poisons Uncovered by Proteomic Screens
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DOI：
10.1016/j.celrep.2014.01.017
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发表时间：
2014-02-01
期刊：
影响因子：
8.8
通讯作者：
Malumbres, Marcos
中科院分区：
文献类型：
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作者：
Eguren, Manuel;Alvarez-Fernandez, Monica;Malumbres, Marcos
后期促进复合物/环体（APC/C）辅因子Cdh 1通过靶向多个细胞周期调节因子进行泛素依赖性降解来调节细胞增殖。Cdh 1的缺乏导致结构和数量染色体畸变，这是基因组不稳定的标志。通过使用蛋白质组学方法在Cdh 1-null细胞和小鼠组织中，我们已经确定了驱动蛋白Eg 5和拓扑异构酶2 α作为Cdh 1参与维持基因组稳定性的目标。这些蛋白质被泛素化，并以Cdh 1依赖的方式通过特定的KEN和D盒降解。尽管Cdh 1-null细胞显示出对Eg 5抑制剂如monastrol的部分抗性，但由于捕获的Top2 α-DNA复合物的水平增加，Cdh 1的缺乏导致对Top2 α毒物的显著敏感性。癌细胞中APC/C的化学抑制导致对Top2 α毒物的敏感性增加。这项工作确定了哺乳动物APC/C-Cdh 1复合物的体内靶点，并揭示了与抗癌治疗相关的合成致死相互作用。
The Anaphase-promoting complex/cyclosome (APC/C) cofactor Cdh1 modulates cell proliferation by targeting multiple cell-cycle regulators for ubiquitin-dependent degradation. Lack of Cdh1 results in structural and numerical chromosome aberrations, a hallmark of genomic instability. By using a proteomic approach in Cdh1-null cells and mouse tissues, we have identified kinesin Eg5 and topoisomerase 2 alpha as Cdh1 targets involved in the maintenance of genomic stability. These proteins are ubiquitinated and degraded through specific KEN and D boxes in a Cdh1-dependent manner. Whereas Cdh1-null cells display partial resistance to Eg5 inhibitors such as monastrol, lack of Cdh1 results in a dramatic sensitivity to Top2 alpha poisons as a consequence of increased levels of trapped Top2 alpha-DNA complexes. Chemical inhibition of the APC/C in cancer cells results in increased sensitivity to Top2 alpha poisons. This work identifies in vivo targets of the mammalian APC/C-Cdh1 complex and reveals synthetic lethal interactions of relevance in anticancer treatments.