Biology subjects

Harry, D.

Publications and source records attributed to Harry, D..

3 recordsLinked to original sources

bioRxiv2025

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

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.

cell biology↗

bioRxiv2022

Mild replication stress causes premature centriole disengagement via a sub-critical Plk1 activity under the control of ATR-Chk1

A tight synchrony between the DNA and centrosome cycle is essential for genomic integrity. Centriole disengagement, which licenses centrosomes for duplication, occurs normally during mitotic exit. We recently demonstrated that mild DNA replication stress in untransformed human cells causes premature centriole disengagement at mitotic entry, leading to transient multipolar spindles that favour chromosome mis-segregation. How mild replication stress accelerate the centrosome cycle at the molecular level remained, however, unclear. Using expansion microscopy, we show that mild replication stress already induces premature centriole disengagement in G2 via the ATR-Chk1 axis of the DNA damage repair pathway. We demonstrate that this results in a subcritical Plk1 kinase activity that is insufficient for rapid mitotic entry. Nevertheless, it primes the pericentriolar matrix for Separase-dependent disassembly causing premature centriole disengagement in G2. We postulate that the differential requirement of Plk1 activity in the DNA and centrosome cycles explains how mild replication stress disrupts the synchrony between both processes and contributes to genomic instability.

cell biology↗

bioRxiv2021

PLK1 controls centriole distal appendage formation and centrobin removal via independent pathways

Centrioles are central structural elements of centrosomes and cilia. They originate as daughter centrioles from existing centrioles in S-phase and reach their full functionality with the formation of distal and subdistal appendages two mitoses later. Current models postulate that the centriolar protein centrobin acts as placeholder for distal appendage proteins that must be removed to complete distal appendage formation. Here, we investigated in non-transformed human epithelial cells the mechanisms controlling centrobin removal and its effect on distal appendage formation. We demonstrate that centrobin is removed from older centrioles due to a higher affinity for the newly born daughter centrioles, under the control of the centrosomal kinase Plk1. Centrobin removal also depends on the presence of subdistal appendage proteins on the oldest centriole. It is, however, not required for distal appendage formation even though this process is equally dependent on Plk1. We conclude that during centriole maturation, Plk1 kinase regulates centrobin removal and distal appendage formation via separate pathways.

cell biology↗