Izumi H, Matsumoto Y, Ikeuchi T, Saya H, Kajii T, Matsuura S
Department of Radiation Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Japan.
Oncogene. 2009 Aug 6;28(31):2806-20. doi: 10.1038/onc.2009.141. Epub 2009 Jun 8.
BubR1 is a critical component of the mitotic checkpoint that delays the onset of anaphase until all chromosomes have established bipolar attachment to the microtubules. We previously reported that mutations of the BUB1B gene (encoding BubR1) caused premature chromatid separation (PCS) syndrome, a condition characterized by constitutional aneuploidy and a high risk of childhood cancer. We here report that the cells from PCS syndrome patients have loss of regulation of the centrosome duplication machinery, resulting in centrosome amplification and multipolar mitosis. PCS syndrome cells show increased activity of Polo-like kinase 1 (Plk1), whose knockdown suppresses centrosome amplification. BubR1 localizes to centrosomes, physically interacts with Plk1 and inhibits Plk1 phosphorylation and its kinase activity during interphase. These results unravel a crucial role of BubR1 in preventing centrosome reduplication through negative regulation of Plk1 in interphase cells.
BubR1是有丝分裂检查点的关键组成部分，它会延迟后期的开始，直到所有染色体都与微管建立双极附着。我们之前报道过，BUB1B基因（编码BubR1）的突变会导致早发性染色单体分离（PCS）综合征，该病症的特征是体质性非整倍体和儿童期患癌风险高。我们在此报道，PCS综合征患者的细胞对中心体复制机制失去调控，导致中心体扩增和多极有丝分裂。PCS综合征细胞显示出Polo样激酶1（Plk1）的活性增加，敲低该激酶可抑制中心体扩增。BubR1定位于中心体，在间期与Plk1发生物理相互作用，并抑制Plk1的磷酸化及其激酶活性。这些结果揭示了BubR1在间期细胞中通过对Plk1的负调控来防止中心体再复制的关键作用。
