PLK1-Mediated Phosphorylation Cascade Activates Mis18 Complex to Ensure Centromere Inheritance
Science article from the JP Arulanandam lab
05.09.2024
Parashara, P*., Medina-Pritchard, B*., Abad, M. A*., Sotelo-Parrilla, P*., Thamkachy, R., Grundei, D., Zou, J., Spanos, C., Kumar, C. N., Basquin, C., Das, V., Yan, Z., Al-Murtadha, A. A., Kelly, D. A., McHug, T., Imhof, A., Rappsilber, J and Jeyaprakash, A. A (2024 Sept 5) PLK1-Mediated Phosphorylation Cascade Activates Mis18 Complex to Ensure Centromere Inheritance. Science (2024) 285 (6713): 1098-1104. Doi: https://doi.org/10.1126/science.ado8270
*equal contribution
Abstract cited directly from the article:
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.