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PLK1-Mediated Phosphorylation Cascade Activates the Mis18 Complex to Ensure Centromere Inheritance
Open accessPreprint — published as 10.1126/science.ado8270 · Paper page
Abstract
Accurate chromosome segregation requires the attachment of spindle microtubules to centromeres, which are epigenetically defined by the enrichment of CENP-A nucleosomes. During DNA replication, existing CENP-A nucleosomes undergo dilution as they get redistributed among the two DNA strands. To preserve centromere identity, CENP-A levels must be restored in a cell-cycle controlled manner orchestrated by the Mis18 complex. Here we provide a comprehensive mechanistic basis for PLK1-mediated licensing of CENP-A loading. We demonstrate that PLK1 interacts with Mis18α and Mis18BP1 subunits of the Mis18 complex by recognising self-primed phosphorylations of Mis18α (S54) and Mis18BP1 (T78 and S93) through its Polo-box binding domain. Disrupting these PLK1 phosphorylations perturbed the centromere recruitment of HJURP and new CENP-A loading. Biochemical and functional analyses show that phosphorylation of Mis18α and subsequent PLK1 binding is required to activate the Mis18α/β complex for robust Mis18α/β-HJURP interaction. Thus, our study reveals key molecular events underpinning the licensing role of PLK1 in ensuring accurate centromere inheritance. One-Sentence Summary: PLK1 phosphorylation cascade licenses CENP-A loading by facilitating HJURP centromere recruitment via Mis18α/β activation.
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Metadata
- Authors
- Parashara, P., Medina-Pritchard, B., Abad, M. A., Sotelo-Parrilla, P., Thamkachy, R., Grundei, D., Zou, J., Das, V., Yan, Z., Kelly, D. A., McHugh, T., Rappsilber, J., & Jeyaprakash, A. A.
- Affiliations
- Wellcome Centre for Cell Biology (GB)
- Ludwig-Maximilians-Universität München (DE)
- Corresponding author
- Parashara, Pragya
- Abad, Maria Alba
- Jeyaprakash, A. Arockia
- ORCID
- Venue
- Science
- Publisher
- openRxiv
- Published
- 2024-02-24
- Volume
- 385
- Issue
- 6713
- Pages
- 1098-1104
- ISSN
- 0036-8075 (ISSN-L)
- OpenAlex
- W4402263012
- Cited by
- 36
- References
- 1
- Citations by year
- 2026: 18 · 2025: 14 · 2024: 4
- FWCI
- 8.05
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by
- Locations
- Science (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (publishedVersion, cc-by)
- Funders
- Wellcome Trust (203149)
- Medical Research Council (MR/X001245/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Chromosomal and Genetic Variations
- Keywords
- PLK1, CENP-A, HJURP, phosphorylation cascade, polo-box domain, chromosome segregation, centromere identity, DNA replication
- MeSH terms
- Centromere Protein A, Polo-Like Kinase 1, Centromere, Chromosomal Proteins, Non-Histone, DNA-Binding Proteins, HeLa Cells, Humans, Phosphorylation, Proto-Oncogene Proteins, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Chromosome Segregation, Adaptor Proteins, Signal Transducing
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