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

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 Malumbres

doi:10.1016/j.celrep.2014.01.017

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

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 Malumbres

32 Citations (Scopus)

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.

Original language	English
Journal	Cell Reports
Volume	6
Issue number	4
Pages (from-to)	670-83
Number of pages	14
ISSN	2211-1247
DOIs	https://doi.org/10.1016/j.celrep.2014.01.017
Publication status	Published - 27 Feb 2014
Externally published	Yes

Keywords

Animals
Antigens, Neoplasm
Binding Sites
Cdh1 Proteins
DNA Topoisomerases, Type II
DNA-Binding Proteins
Genomic Instability
HEK293 Cells
HeLa Cells
Humans
Kinesin
Mice
Protein Binding
Proteome
Pyrimidines
Thiones
Topoisomerase II Inhibitors
Ubiquitination
Xenopus

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2014.01.017

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Eguren, M., Álvarez-Fernández, M., García, F., López-Contreras, A. J., Fujimitsu, K., Yaguchi, H., Luque-García, J. L., Fernández-Capetillo, O., Muñoz, J., Yamano, H., & Malumbres, M. (2014). A synthetic lethal interaction between APC/C and topoisomerase poisons uncovered by proteomic screens. Cell Reports, 6(4), 670-83. https://doi.org/10.1016/j.celrep.2014.01.017

Eguren, M, Álvarez-Fernández, M, García, F, López-Contreras, AJ, Fujimitsu, K, Yaguchi, H, Luque-García, JL, Fernández-Capetillo, O, Muñoz, J, Yamano, H & Malumbres, M 2014, 'A synthetic lethal interaction between APC/C and topoisomerase poisons uncovered by proteomic screens', Cell Reports, vol. 6, no. 4, pp. 670-83. https://doi.org/10.1016/j.celrep.2014.01.017

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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.",

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AB - 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.

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JO - Cell Reports

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ER -

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

Abstract

Keywords

UN SDGs

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