研究人员表示，准确的染色体分离需要微管附着到由CENP-A核小体富集定义的着丝粒上。在DNA复制过程中，CENP-A核小体会稀释。为了保持着丝粒的身份，必须以细胞周期调控的方式恢复适量的CENP-A，这一过程由Mis18复合物（Mis18α-Mis18β-Mis18BP1）协调。
研究人员展示了PLK1通过其Polo-box结构域识别Mis18α（Ser54）和Mis18BP1（Thr78和Ser93）的自激活磷酸化，与Mis18复合物相互作用。破坏这些磷酸化会扰乱CENP-A伴侣蛋白HJURP的着丝粒招募及新CENP-A的加载。生化和功能分析显示，Mis18α的磷酸化和PLK1的结合是激活Mis18α-Mis18β并促进Mis18复合物-HJURP相互作用所需的。因此，该研究揭示了PLK1在确保准确着丝粒遗传中的许可作用的关键分子事件。
附：英文原文
Title: PLK1-mediated phosphorylation cascade activates Mis18 complex to ensure centromere inheritance
Author: Pragya Parashara, Bethan Medina-Pritchard, Maria Alba Abad, Paula Sotelo-Parrilla, Reshma Thamkachy, David Grundei, Juan Zou, Christos Spanos, Chandni Natalia Kumar, Claire Basquin, Vimal Das, Zhaoyue Yan, Asma Abdullah Al-Murtadha, David A. Kelly, Toni McHugh, Axel Imhof, Juri Rappsilber, A. Arockia Jeyaprakash
Issue&Volume: 2024-09-06
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.
DOI: ado8270
Source: https://www.science.org/doi/10.1126/science.ado8270