Joanna R. Kelly 1 , 6 , Silvia Martini 1 , Nicola Brownlow 1 , 7 , Dhira Joshi 2 , Stefania Federico 2 , Shirin Jamshidi 3 , Svend Kjaer 4 , Nicola Lockwood 1 , Khondaker Miraz Rahmen 3 , Franca Fraternali 5 , Peter J. Parker , 1 , 3 , Tanya N. Soliman , 1 , 8
13 March 2020
The Aurora B abscission checkpoint delays cytokinesis until resolution of DNA trapped in the cleavage furrow. This process involves PKCε phosphorylation of Aurora B S227. Assessing if this PKCε-Aurora B module provides a more widely exploited genome-protective control for the cell cycle, we show Aurora B phosphorylation at S227 by PKCε also occurs during mitosis. Expression of Aurora B S227A phenocopies inhibition of PKCε in by-passing the delay and resolution at anaphase entry that is associated with non-disjunction and catenation of sister chromatids. Implementation of this anaphase delay is reflected in PKCε activation following cell cycle dependent cleavage by caspase 7; knock-down of caspase 7 phenocopies PKCε loss, in a manner rescued by ectopically expressing/generating a free PKCε catalytic domain. Molecular dynamics indicates that Aurora B S227 phosphorylation induces conformational changes and this manifests in a profound switch in specificity towards S29 TopoIIα phosphorylation, a response necessary for catenation resolution during mitosis.
In mitosis, Aurora B switches substrate specificity in response to phosphorylation of S227 in the activation loop by a cell cycle-processed active fragment of PKCε. Here, the authors show that this switch protects from chromosome non-disjunction by delaying anaphase entry and promoting TopoIIα-dependent resolution.