Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
Proteomics Unit, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
Cell Rep. 2014 Feb 27;6(4):670-83. doi: 10.1016/j.celrep.2014.01.017. Epub 2014 Feb 6.
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 2α 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 Top2α poisons as a consequence of increased levels of trapped Top2α-DNA complexes. Chemical inhibition of the APC/C in cancer cells results in increased sensitivity to Top2α poisons. This work identifies in vivo targets of the mammalian APC/C-Cdh1 complex and reveals synthetic lethal interactions of relevance in anticancer treatments.
后期促进复合物/细胞周期素体（APC/C）辅助因子 Cdh1 通过靶向多种细胞周期调节剂进行泛素依赖性降解来调节细胞增殖。Cdh1 的缺失会导致结构和数量上的染色体异常，这是基因组不稳定性的标志。通过在 Cdh1 缺失细胞和小鼠组织中使用蛋白质组学方法，我们已经鉴定出驱动蛋白 Eg5 和拓扑异构酶 2α 是 Cdh1 的靶标，它们参与维持基因组稳定性。这些蛋白质通过特定的 KEN 和 D 盒在 Cdh1 依赖性方式下被泛素化和降解。虽然 Cdh1 缺失细胞对 Eg5 抑制剂（如单奈立林）表现出部分耐药性，但由于结合的 Top2α-DNA 复合物水平增加，Cdh1 的缺失导致对 Top2α 毒物的敏感性显著增加。在癌细胞中化学抑制 APC/C 会导致对 Top2α 毒物的敏感性增加。这项工作鉴定了哺乳动物 APC/C-Cdh1 复合物的体内靶标，并揭示了在癌症治疗中具有相关性的合成致死相互作用。
