Polo-like Kinase 1 Licenses CENP-A Deposition at Centromeres

• Published in: Cell 2014-07, Vol.158 (2), p.397-411
• Main Authors: McKinley, Kara L., Cheeseman, Iain M.
• Format: Article
• Language: English
• Subjects: Autoantigens - metabolism; Cell Cycle; Cell Cycle Proteins - metabolism; Cell Line; Centromere - metabolism; Centromere Protein A; Chromosomal Proteins, Non-Histone - metabolism; Cyclin-Dependent Kinases - metabolism; Genomic Instability; HeLa Cells; Humans; Polo-Like Kinase 1; Protein Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins - metabolism
• ISSN: 0092-8674; 1097-4172
• 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. [Display omitted] •Polo-like kinase 1 (Plk1) is required for CENP-A deposition in human cells•Plk1 phosphorylates the Mis18 complex to promote its localization•Cyclin-dependent kinase (CDK) inhibits Mis18 complex assembly•Bypassing Plk1 and CDK regulation causes constitutive CENP-A deposition Timely and accurate association of CENP-A on human chromosomes during the cell cycle depends on independent regulation of the Mis18 assembly complex by polo-like kinase 1 and by CDK.