Derive Nicolas, Landmann Cedric, Montembault Emilie, Claverie Marie-Charlotte, Pierre-Elies Priscillia, Goutte-Gattat Damien, Founounou Nabila, McCusker Derek, Royou Anne
Université de Bordeaux, Institut Européen de Chimie et Biologie, Institut de Biochimie et Génétique Cellulaires, Unité Mixte de Recherche 5095, 33607 Pessac, France Centre National de la Recherche Scientifique, Institut Européen de Chimie et Biologie, Institut de Biochimie et Génétique Cellulaires, Unité Mixte de Recherche 5095, 33607 Pessac, France.
Université de Bordeaux, Institut Européen de Chimie et Biologie, Institut de Biochimie et Génétique Cellulaires, Unité Mixte de Recherche 5095, 33607 Pessac, France Centre National de la Recherche Scientifique, Institut Européen de Chimie et Biologie, Institut de Biochimie et Génétique Cellulaires, Unité Mixte de Recherche 5095, 33607 Pessac, France
J Cell Biol. 2015 Nov 9;211(3):517-32. doi: 10.1083/jcb.201504059.
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 chromosomes 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.
有丝分裂期间DNA双链断裂的存在对细胞来说尤其具有挑战性，因为这会产生缺乏着丝粒的断裂染色体。这种情况会导致基因组不稳定，原因是断裂片段错误地分离到子细胞中。我们最近发现了一个过程，通过这个过程，断裂的染色体通过BubR1依赖的两个断裂染色体末端的连接而被忠实地传递。然而，BubR1在断裂染色体上募集和发挥功能的潜在机制在很大程度上尚不清楚。我们发现，BubR1需要与Bub3相互作用才能定位在断裂的染色体片段上，并介导它们的正确分离。我们还发现，E3泛素连接酶后期促进复合物/细胞周期体（APC/C）的辅助因子Cdc20以BubR1 KEN盒依赖的方式在DNA断裂处积累。一种用于检测APC/C活性的生物传感器显示，在分离的断裂染色体周围，APC/C存在BubR1依赖的局部抑制。因此，我们提出，断裂DNA上的Bub3 - BubR1复合物通过隔离Cdc20在局部抑制APC/C，从而促进断裂染色体的正确传递。
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