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Bub3–BubR1-dependent sequestration of Cdc20Fizzy at DNA breaks facilitates the correct segregation of broken chromosomes

Nicolas Derive1,2,a, Cédric Landmann1,2,a, Émilie Montembault1,2, Marie-Charlotte Claverie1,2, Priscillia Pierre-Eliès1,2, Damien Goutte-Gattat1,2, Nabila Founounou1,2, Derek McCusker1,2, and Anne Royou1,2,b

1Université de Bordeaux

2Institut de Biochimie et Génétique Cellulaires, CNRS UMR 5095, 33607 Pessac, France

aThese authors contributed equally to this work.

bCorresponding author: a.royou@iecb.u-bordeaux.fr

This article was published in the Journal of Cell Biology under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license on November 9, 2015. It is available under the terms of a Creative Commons Attribution–Noncommercial–Share Alike 3.0 Unported license.

J. Cell Biol.,211(3):517–532. doi:10.1083/jcb.201504059 [full text]

Abstract

The presence of DNA double-strand breaks during mitosis is particularly challenging for the cell, as it produces broken chromosomes lacking a centromere. This situation can cause genomic instability resulting from improper segregation of the broken fragments into daughter cells. We recently uncovered a process by which broken chromosomes are faithfully transmitted via the BubR1-dependent tethering of the two broken chromosome ends. However, the mechanisms underlying BubR1 recruitment and function on broken chromosome fragments were largely unknown. We show that BubR1 requires interaction with Bub3 to localize on the broken chromosome fragments and to mediate their proper segregation. We also find that Cdc20, a cofactor of the E3 ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C), accumulates on DNA breaks in a BubR1 KEN box-dependent manner. A biosensor for APC/C activity demonstrates a BubR1-dependent local inhibition of APC/C around the segregating broken chromosome. We therefore propose that the Bub3-BubR1 complex on broken DNA inhibits the APC/C locally via the sequestration of Cdc20, thus promoting proper transmission of broken chromosomes.

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