Whitehead Institute and Department of Biology, MIT, Nine Cambridge Center, Cambridge, MA 02142, USA.
Whitehead Institute and Department of Biology, MIT, Nine Cambridge Center, Cambridge, MA 02142, USA.
Cell. 2014 Jul 17;158(2):397-411. doi: 10.1016/j.cell.2014.06.016.
To ensure the stable transmission of the genome during vertebrate cell division, the mitotic spindle must attach to a single locus on each chromosome, termed the centromere. The fundamental requirement for faithful centromere inheritance is the controlled deposition of the centromere-specifying histone, CENP-A. However, the regulatory mechanisms that ensure the precise control of CENP-A deposition have proven elusive. Here, we identify polo-like kinase 1 (Plk1) as a centromere-localized regulator required to initiate CENP-A deposition in human cells. We demonstrate that faithful CENP-A deposition requires integrated signals from Plk1 and cyclin-dependent kinase (CDK), with Plk1 promoting the localization of the key CENP-A deposition factor, the Mis18 complex, and CDK inhibiting Mis18 complex assembly. By bypassing these regulated steps, we uncoupled CENP-A deposition from cell-cycle progression, resulting in mitotic defects. Thus, CENP-A deposition is controlled by a two-step regulatory paradigm comprised of Plk1 and CDK that is crucial for genomic integrity.
为确保脊椎动物细胞分裂过程中基因组的稳定传递，有丝分裂纺锤体必须附着在每条染色体上的一个称为着丝粒的单一位置上。忠实传递着丝粒的基本要求是着丝粒特异性组蛋白 CENP-A 的受控沉积。然而，已证明确保 CENP-A 沉积精确控制的调节机制难以捉摸。在这里，我们确定 Polo 样激酶 1 (Plk1) 是一种着丝粒定位调节剂，在人类细胞中启动 CENP-A 沉积是必需的。我们证明，忠实的 CENP-A 沉积需要 Plk1 和细胞周期蛋白依赖性激酶 (CDK) 的综合信号，其中 Plk1 促进关键的 CENP-A 沉积因子 Mis18 复合物的定位，而 CDK 抑制 Mis18 复合物的组装。通过绕过这些受调控的步骤，我们将 CENP-A 沉积与细胞周期进程解耦，导致有丝分裂缺陷。因此，CENP-A 沉积受 Plk1 和 CDK 组成的两步调节范例控制，这对于基因组完整性至关重要。
