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

Polo-like kinase 1 (Plk1) regulates multiple cell- and centrosome-cycle steps, 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 Cep192 and Cenexin. However, whether these Plk1 coactivators differentially regulate the Plk1-dependent processes is unknown. Here, we show that each Plk1 co-activator controls different cell cycle steps via distinct Plk1 pools in human cells. While Bora is the main driver for mitotic entry, DNA recovery and centrosome maturation, centriole disengagement is mainly under the control of Cep192 and Cenexin. Moreover, we find that Plk1 drives S-phase progression by favouring replication origin firing, under the main control of Cep192. Our results thus uncover the complexity of Plk1 activation regulatory network, where distinct upstream activators dictate its activity in a context dependent manner.