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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Neoplasm / chemistry
  • Antigens, Neoplasm / metabolism
  • Binding Sites
  • Cdh1 Proteins / genetics
  • Cdh1 Proteins / metabolism*
  • DNA Topoisomerases, Type II / chemistry
  • DNA Topoisomerases, Type II / metabolism
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / metabolism
  • Genomic Instability
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Kinesin / chemistry
  • Kinesin / metabolism
  • Mice
  • Protein Binding
  • Proteome / metabolism*
  • Pyrimidines / pharmacology*
  • Thiones / pharmacology*
  • Topoisomerase II Inhibitors / pharmacology*
  • Ubiquitination
  • Xenopus

Substances

  • Antigens, Neoplasm
  • Cdh1 Proteins
  • DNA-Binding Proteins
  • Fzr1 protein, mouse
  • Proteome
  • Pyrimidines
  • Thiones
  • Topoisomerase II Inhibitors
  • monastrol
  • Kif11 protein, mouse
  • Kinesin
  • DNA Topoisomerases, Type II