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 Citationer (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.

Originalsprog	Engelsk
Tidsskrift	Cell Reports
Vol/bind	6
Udgave nummer	4
Sider (fra-til)	670-83
Antal sider	14
ISSN	2211-1247
DOI	https://doi.org/10.1016/j.celrep.2014.01.017
Status	Udgivet - 27 feb. 2014
Udgivet eksternt	Ja

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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, bind 6, nr. 4, s. 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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AU - Fujimitsu, Kazuyuki

AU - Yaguchi, Hiroko

AU - Luque-García, José Luis

AU - Fernández-Capetillo, Oscar

AU - Muñoz, Javier

AU - Yamano, Hiroyuki

AU - Malumbres, Marcos

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N2 - 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.

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.

KW - Animals

KW - Antigens, Neoplasm

KW - Binding Sites

KW - Cdh1 Proteins

KW - DNA Topoisomerases, Type II

KW - DNA-Binding Proteins

KW - Genomic Instability

KW - HEK293 Cells

KW - HeLa Cells

KW - Humans

KW - Kinesin

KW - Mice

KW - Protein Binding

KW - Proteome

KW - Pyrimidines

KW - Thiones

KW - Topoisomerase II Inhibitors

KW - Ubiquitination

KW - Xenopus

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DO - 10.1016/j.celrep.2014.01.017

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VL - 6

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EP - 683

JO - Cell Reports

JF - Cell Reports

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ER -

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

Abstract

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