PLK1-mediated phosphorylation cascade activates Mis18 complex to ensure centromere inheritance

Affiliations

• Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh EH9 3BF, UK.
• Gene Center Munich, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
• Protein Analysis Unit, Biomedical Centre Munich, Faculty of Medicine, Ludwig-Maximilians-University, 82152 Munich, Germany.
• Department of Structural Biology, Max Planck Institute of Biochemistry, D-82152 Martinsried, Germany.
• Institute of Biotechnology, Technische Universität Berlin, 13355 Berlin, Germany.

PMID:  39236175  DOI: 10.1126/science.ado8270

Abstract

Accurate chromosome segregation requires the attachment of microtubules to centromeres, epigenetically defined by the enrichment of CENP-A nucleosomes. During DNA replication, CENP-A nucleosomes undergo dilution. To preserve centromere identity, correct amounts of CENP-A must be restored in a cell cycle-controlled manner orchestrated by the Mis18 complex (Mis18α-Mis18β-Mis18BP1). We demonstrate here that PLK1 interacts with the Mis18 complex by recognizing self-primed phosphorylations of Mis18α (Ser54) and Mis18BP1 (Thr78 and Ser93) through its Polo-box domain. Disrupting these phosphorylations perturbed both centromere recruitment of the CENP-A chaperone HJURP and new CENP-A loading. Biochemical and functional analyses showed that phosphorylation of Mis18α and PLK1 binding were required to activate Mis18α-Mis18β and promote Mis18 complex-HJURP interaction. Thus, our study reveals key molecular events underpinning the licensing role of PLK1 in ensuring accurate centromere inheritance.

染色体的准确分离依赖于微管与由富集的CENP-A核小体表观遗传定义的着丝粒的结合。在DNA复制过程中，CENP-A核小体会被稀释。为维持着丝粒的存在，必须通过细胞周期调控机制恢复适量的CENP-A，这一过程由Mis18复合体（Mis18α-Mis18β-Mis18BP1）协调。我们证明PLK1通过其Polo-box结构域识别Mis18α（Ser54）和Mis18BP1（Thr78和Ser93）的自引发磷酸化，与Mis18复合体相互作用。破坏这些磷酸化会扰乱CENP-A伴侣HJURP的着丝粒招募和CENP-A的组装。生化与功能分析表明，Mis18α的磷酸化和PLK1结合对于激活Mis18α-Mis18β及促进Mis18复合体与HJURP的相互作用是必需的。因此，我们的研究揭示了PLK1在确保准确的着丝粒遗传中的关键分子事件。