2026-04-27T07:46:31Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/113992024-11-29T18:49:20Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597
Repisalud
author
Eguren, Manuel
author
Alvarez Fernandez, Monica
author
García, Fernando
author
López-Contreras, Andrés J
author
Fujimitsu, Kazuyuki
author
Yaguchi, Hiroko
author
Luque-García, José Luis
author
Yamano, Hiroyuki
author
Fernandez-Capetillo, Oscar
author
Malumbres Martinez, Marcos
author
Munoz, Javier
funder
Ministerio de Ciencia e Innovación (España)
funder
Asociación Española Contra el Cáncer
funder
Howard Hughes Medical Institute
funder
Unión Europea. Comisión Europea. European Research Council (ERC)
funder
Fundación Ramón Areces
funder
Comunidad de Madrid (España)
funder
Unión Europea
funder
Worldwide Cancer Research
funder
Cancer Research UK (Reino Unido)
2020-11-23T11:47:39Z
2020-11-23T11:47:39Z
2014-02-27
Cell Rep. 2014 ;6(4):670-83.
http://hdl.handle.net/20.500.12105/11399
24508461
10.1016/j.celrep.2014.01.017
Cell reports
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.
eng
A synthetic lethal interaction between APC/C and topoisomerase poisons uncovered by proteomic screens.
journal article
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