Cell Reports - A Synthetic Lethal Interaction between APC/C and Topoisomerase Poisons Uncovered by Proteomic Screens

Cell Reports - 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

Cell Reports, 06 February 2014
Copyright © 2014 The Authors
10.1016/j.celrep.2014.01.017
This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivative Works License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited.

Authors

Manuel Eguren,Mónica Álvarez-Fernández,Fernando García,Andrés J. López-Contreras,Kazuyuki Fujimitsu,Hiroko Yaguchi,José Luis Luque-García,Oscar Fernández-Capetillo,Javier Muñoz,Hiroyuki Yamano,Marcos MalumbresSee Affiliations

• Highlights
• Several proteomic screens for APC/C-Cdh1 substrates identify Eg5 and Top2α
• Overexpression of Eg5 in Cdh1-null cells results in protection against monastrol
• Genetic ablation of Cdh1 results in increased susceptibility to Top2α poisons
• Chemical inhibition of the APC/C sensitizes tumor cells to Top2α poisons

Summary

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.