Division of Centrosome Biology, National Institute of Genetics, Mishima, Shizuoka, 411-8540, Japan.
Department of Genetics, School of Life Science, The Graduate University for Advanced Studies (SOKENDAI), Hayama, Kanagawa, 240-0193, Japan.
Nat Commun. 2019 Feb 25;10(1):931. doi: 10.1038/s41467-019-08862-2.
Centriole duplication occurs once per cell cycle to ensure robust formation of bipolar spindles and chromosome segregation. Each newly-formed daughter centriole remains connected to its mother centriole until late mitosis. The disengagement of the centriole pair is required for centriole duplication. However, the mechanisms underlying centriole engagement remain poorly understood. Here, we show that Cep57 is required for pericentriolar material (PCM) organization that regulates centriole engagement. Depletion of Cep57 causes PCM disorganization and precocious centriole disengagement during mitosis. The disengaged daughter centrioles acquire ectopic microtubule-organizing-center activity, which results in chromosome mis-segregation. Similar defects are observed in mosaic variegated aneuploidy syndrome patient cells with cep57 mutations. We also find that Cep57 binds to the well-conserved PACT domain of pericentrin. Microcephaly osteodysplastic primordial dwarfism disease pericentrin mutations impair the Cep57-pericentrin interaction and lead to PCM disorganization. Together, our work demonstrates that Cep57 provides a critical interface between the centriole core and PCM.
中心体复制发生在每个细胞周期一次，以确保两极纺锤体的稳健形成和染色体分离。每个新形成的子中心体在后期有丝分裂之前仍与其母中心体相连。中心体对的脱离是中心体复制所必需的。然而，中心体结合的机制仍知之甚少。在这里，我们表明 Cep57 是中心粒周围物质 (PCM) 组织所必需的，PCM 组织调节中心粒结合。Cep57 的耗竭导致 PCM 解聚和有丝分裂期间中心体过早脱离。脱离的子中心体获得异位微管组织中心活性，导致染色体错误分离。在具有 cep57 突变的镶嵌斑驳非整倍体综合征患者细胞中观察到类似的缺陷。我们还发现 Cep57 与中心粒周围蛋白的高度保守的 PACT 结构域结合。小头畸形-骨发育不良-原基性侏儒症疾病的中心粒周围蛋白突变会损害 Cep57-中心粒周围蛋白的相互作用，并导致 PCM 解聚。总之，我们的工作表明 Cep57 为中心体核心和 PCM 之间提供了一个关键界面。
