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Cell Rep. 2014 Feb 27;6(4):670-83. doi: 10.1016/j.celrep.2014.01.017. Epub 2014 Feb 6.

A synthetic lethal interaction between APC/C and topoisomerase poisons uncovered by proteomic screens.

Author information

1
Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
2
Proteomics Unit, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
3
Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
4
Cell Cycle Control Group, University College London Cancer Institute, London WC1E 6BT, UK.
5
Department of Analytical Chemistry, Complutense University of Madrid, Madrid 28015, Spain.
6
Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain. Electronic address: malumbres@cnio.es.

Abstract

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.

PMID:
24508461
DOI:
10.1016/j.celrep.2014.01.017
[Indexed for MEDLINE]
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