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.