PLK1-mediated phosphorylation cascade activates Mis18 complex to ensure centromere inheritance
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<sup>54</sup>) and Mis18BP1 (Thr<sup>78</sup> and Ser<sup>93</sup>) 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.
Authors
- Toni McHugh (ORCID: https://orcid.org/0000-0002-5212-3868)
- Asma Abdullah Abdulwahab Al-Murtadha
- Christos Spanos (ORCID: https://orcid.org/0000-0002-4376-8242)
- Juan Zou (ORCID: https://orcid.org/0000-0003-2594-6217)
- Chandni Kumar (ORCID: https://orcid.org/0000-0002-7872-9251)
- David Grundei (ORCID: https://orcid.org/0000-0001-9161-2624)
- Maria Alba Abad (ORCID: https://orcid.org/0000-0002-8816-1524)
- David A. Kelly (ORCID: https://orcid.org/0000-0002-3021-8495)
- Paula Sotelo‐Parrilla (ORCID: https://orcid.org/0000-0002-6333-1005)
- Bethan Medina‐Pritchard (ORCID: https://orcid.org/0000-0002-6736-9203)
- Claire Basquin
- Juri Rappsilber (ORCID: https://orcid.org/0000-0001-5999-1310)
- Axel Imhof (ORCID: https://orcid.org/0000-0003-2993-8249)
- Pragya Parashara (ORCID: https://orcid.org/0009-0006-2357-7218)
- Zhaoyue Yan
- A. Arockia Jeyaprakash
- Reshma Thamkachy
- Vimal Das
Institutions
- Center for Integrated Protein Science Munich (DE)
- Wellcome Centre for Cell Biology (GB)
- Max Planck Institute of Biochemistry (DE)
- Technische Universität Berlin (DE)
- Ludwig-Maximilians-Universität München (DE)
- University of Edinburgh (GB)
Publication Details
- Journal
- Science
- Published
- 2024-09-05
- DOI
- https://doi.org/10.1126/science.ado8270
- Citations
- 28
- Primary Topic
- Chromosomal and Genetic Variations
- Type
- article
- Field-Weighted Citation Impact
- 16.79