Bora, CEP192 and Cenexin activate different Plk1 pools and regulate distinct cell and centrosome cycle transitions

Abstract Polo-like kinase 1 (Plk1) regulates multiple steps of the cell and centrosome cycle, including mitotic entry, DNA-damage recovery, centrosome maturation and centriole disengagement. Plk1 activity depends on several independent cofactors, such as the cytoplasmic Bora, and the centrosomal proteins Cep192 and Cenexin. However, whether these Plk1 coactivators differentially regulate the Plk1-dependent processes is unknown. Here, we show that each Plk1 coactivator controls different cell cycle steps via distinct Plk1 pools in human cells. While Bora is the main driver for mitotic entry, DNA-damage recovery and centrosome maturation, centriole disengagement is mainly regulated by Cep192 and Cenexin. Moreover, we find that Plk1 and Cep192 drive S-phase progression by promoting replication origin firing. Our results thus uncover the complexity of the Plk1 activation regulatory network, in which distinct upstream activators dictate its activity in a context-dependent manner.