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 typically seen in cancer cells causes premature centriole disengagement in untransformed mitotic human cells, leading to transient multipolar spindles that favour chromosome missegregation. How mild replication stress accelerates the centrosome cycle at the molecular level remained, however, unclear. Using ultrastructure expansion microscopy, we show that mild replication stress induces premature centriole disengagement already in G2 via the ATR-Chk1 axis of the DNA damage repair pathway. This results in a sub-critical Plk1 kinase activity that primes the pericentriolar matrix for Separase-dependent disassembly but is insufficient for rapid mitotic entry, causing premature centriole disengagement in G2. We postulate that the differential requirement of Plk1 activity for the DNA and centrosome cycles explains how mild replication stress disrupts the synchrony between both processes and contributes to genomic instability. Mild replication stress leads to premature centriole disengagement while delaying mitotic onset. Here, Dwivedi et al. demonstrate that this results from sub-critical Plk1 kinase activity, enabling centrosome cycling but impeding rapid mitotic entry.

Automated summary

This study reveals that mild replication stress leads to premature centriole disengagement while delaying mitotic onset. This is caused by sub-critical Plk1 kinase activity, enabling centrosome cycling but impeding rapid mitotic entry.