Mitotic Entry Upon Topo Ii Catalytic Inhibition Is Controlled By Chk1 And Plk1

Catalytic inhibition of topoisomerase II during G2 phase delays onset of mitosis due to the activation of the so-called decatenation checkpoint. This checkpoint is less known compared with the extensively studied G2 DNA damage checkpoint and is partially compromised in many tumor cells. We recently identified MCPH1 as a key regulator that confers cells with the capacity to adapt to the decatenation checkpoint. In the present work, we have explored the contributions of checkpoint kinase 1 (Chk1) and polo-like kinase 1 (Plk1), in order to better understand the molecular basis of decatenation checkpoint. Our results demonstrate that Chk1 function is required to sustain the G2 arrest induced by catalytic inhibition of Topo II. Interestingly, Chk1 loss of function restores adaptation in cells lacking MCPH1. Furthermore, we demonstrate that Plk1 function is required to bypass the decatenation checkpoint arrest in cells following Chk1 inhibition. Taken together, our data suggest that MCPH1 is critical to allow checkpoint adaptation by counteracting Chk1-mediated inactivation of Plk1. Importantly, we also provide evidence that MCPH1 function is not required to allow recovery from this checkpoint, which lends support to the notion that checkpoint adaptation and recovery are different mechanisms distinguished in part by specific effectors.