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

• 成果类型: Article
• 署名作者: Parashara, Pragya; Medina-Pritchard, Bethan; Abad, Maria Alba; Sotelo-Parrilla, Paula; Thamkachy, Reshma; Grundei, David; Zou, Juan; Spanos, Christos; Kumar, Chandni Natalia; Basquin, Claire; Das, Vimal; Yan, Zhaoyue; Al-Murtadha, Asma Abdullah; Kelly, David A.; McHugh, Toni; Imhof, Axel; Rappsilber, Juri; Jeyaprakash, A. Arockia
• 署名单位: University of Edinburgh; University of Munich; University of Munich; Max Planck Society; Technical University of Berlin; University of Washington; University of Washington Seattle
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-9167
• DOI: 10.1126/science.ado8270
• 发表日期: 2024-09-06
• 页码: 1098-1104
• 关键词: cenp-a; molecular-basis; RECRUITMENT; deposition; maintenance; m18bp1; domain; hjurp

摘要

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 (Mis18 alpha-Mis18 beta-Mis18BP1). We demonstrate here that PLK1 interacts with the Mis18 complex by recognizing self-primed phosphorylations of Mis18 alpha (Ser(54)) and Mis18BP1 (Thr(78) and Ser(93)) 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 Mis18 alpha and PLK1 binding were required to activate Mis18 alpha-Mis18 beta and promote Mis18 complex-HJURP interaction. Thus, our study reveals key molecular events underpinning the licensing role of PLK1 in ensuring accurate centromere inheritance.