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

Author:

Parashara Pragya1ORCID,Medina-Pritchard Bethan1ORCID,Abad Maria Alba1,Sotelo-Parrilla Paula2ORCID,Thamkachy Reshma1,Grundei David2ORCID,Zou Juan1ORCID,Spanos Christos1ORCID,Kumar Chandni Natalia3ORCID,Basquin Claire4ORCID,Das Vimal1,Yan Zhaoyue1,Al-Murtadha Asma Abdullah1ORCID,Kelly David A.1ORCID,McHugh Toni1ORCID,Imhof Axel4ORCID,Rappsilber Juri15ORCID,Jeyaprakash A. Arockia12ORCID

Affiliation:

1. Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh EH9 3BF, UK.

2. Gene Center Munich, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.

3. Protein Analysis Unit, Biomedical Centre Munich, Faculty of Medicine, Ludwig-Maximilians-University, 82152 Munich, Germany.

4. Department of Structural Biology, Max Planck Institute of Biochemistry, D-82152 Martinsried, Germany.

5. Institute of Biotechnology, Technische Universität Berlin, 13355 Berlin, Germany.

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 (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 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.

Publisher

American Association for the Advancement of Science (AAAS)

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