title: A synthetic lethal interaction between APC/C and topoisomerase poisons uncovered by proteomic screens.
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.
authors: Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors: Manuel
authors: M
authors: Eguren
authors: Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors: Mónica
authors: M
authors: Álvarez-Fernández
authors: Proteomics Unit, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors: Fernando
authors: F
authors: García
authors: Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors: Andrés J
authors: AJ
authors: López-Contreras
authors: Cell Cycle Control Group, University College London Cancer Institute, London WC1E 6BT, UK.
authors: Kazuyuki
authors: K
authors: Fujimitsu
authors: Cell Cycle Control Group, University College London Cancer Institute, London WC1E 6BT, UK.
authors: Hiroko
authors: H
authors: Yaguchi
authors: Department of Analytical Chemistry, Complutense University of Madrid, Madrid 28015, Spain.
authors: José Luis
authors: JL
authors: Luque-García
authors: Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors: Oscar
authors: O
authors: Fernández-Capetillo
authors: Proteomics Unit, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors: Javier
authors: J
authors: Muñoz
authors: Cell Cycle Control Group, University College London Cancer Institute, London WC1E 6BT, UK.
authors: Hiroyuki
authors: H
authors: Yamano
authors: Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain. Electronic address: malumbres@cnio.es.
authors: Marcos
authors: M
authors: Malumbres
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D064200:Cdh1 Proteins / Q000235:genetics / Q000378:metabolism*; D004250:DNA Topoisomerases, Type II / Q000737:chemistry / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D042822:Genomic Instability; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D016547:Kinesins / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D011485:Protein Binding; D020543:Proteome / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*; D013871:Thiones / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology*; D054875:Ubiquitination; D014981:Xenopus
chemical_list: D000951:Antigens, Neoplasm; D064200:Cdh1 Proteins; D004268:DNA-Binding Proteins; C577585:Fzr1 protein, mouse; D020543:Proteome; D011743:Pyrimidines; D013871:Thiones; D059005:Topoisomerase II Inhibitors; C400223:monastrol; C521052:Kif11 protein, mouse; D016547:Kinesins; D004250:DNA Topoisomerases, Type II