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

Parashara, P., Medina-Pritchard, B., Alba Abad, M., Sotelo-Parrilla, P., Thamkachy, R., Grundei, D., Zou, J., Spanos, C., Kumar C.N. and Jeyaprakash, A.A.

By Dipika Mishra, Akiyoshi Lab

The centromere is critical for eukaryotic chromosome segregation as it forms the platform for kinetochore assembly required for the attachment of chromosomes to microtubules. The centromere is epigenetically specified by the enrichment of a histone H3 variant called CENP-A. Interestingly, during each round of cell division, the levels of CENP-A at the centromere decrease by half. To compensate for this loss and to ensure centromere identity, a defined amount of CENP-A needs to be replenished back at the centromere. In humans, this occurs through the Mis18 complex (composed of Mis18a, Mis18b and Mis18BP1) that recruits the CENP-A specific chaperone, HJURP, to deposit CENP-A during G1 phase, a process which is regulated by PLK1. Despite extensive research in the field, the molecular mechanisms for PLK1-mediated regulation of CENP-A deposition remained obscure.

Research in the JP lab, published in Science, sheds light on this fundamental question in the field. Their research highlights the function of PLK1 in mediating a cascade of phosphorylations that allows the Mis18 complex to act as a guide, controlling when HJURP binds to the centromere and ensuring CENP-A is loaded at the right place and time during cell division. Through biochemical, structural and cell-based studies, they demonstrate that PLK1 directly interacts with Mis18a and Mis18BP1 through self-priming phosphorylations that activate the Mis18 complex and allow its binding to HJURP. This novel work provides critical insights into the molecular mechanism of CENP-A deposition and addresses one of the key questions of eukaryotic chromosome segregation mechanism.