The Aurora B specificity switch is required to protect from non-disjunction at the metaphase/anaphase transition

• Published in: Nature communications 2020-03, Vol.11 (1), p.1396-1396, Article 1396
• Main Authors: Kelly, Joanna R., Martini, Silvia, Brownlow, Nicola, Joshi, Dhira, Federico, Stefania, Jamshidi, Shirin, Kjaer, Svend, Lockwood, Nicola, Rahman, Khondaker Miraz, Fraternali, Franca, Parker, Peter J., Soliman, Tanya N.
• Format: Article
• Language: English
• Subjects: 631/45/275; 631/80/458/1733; 631/80/641/1655; 631/80/86; 96/95; Abscission; Anaphase; Anaphase - genetics; Anaphase - physiology; Aurora B protein; Aurora Kinase B - chemistry; Aurora Kinase B - genetics; Aurora Kinase B - metabolism; Caspase 7 - metabolism; Caspase-7; Catenation; Cell activation; Cell cycle; Cell Cycle Proteins - metabolism; Chromatids; Chromatids - metabolism; Chromatin; Chromosomes; Chromosomes - metabolism; Cleavage; Cytokinesis; Deoxyribonucleic acid; Disjunction; DNA; Genomes; HEK293 Cells; Humanities and Social Sciences; Humans; Metaphase; Metaphase - genetics; Metaphase - physiology; Mitosis; Mitosis - genetics; Mitosis - physiology; Molecular dynamics; Molecular Dynamics Simulation; multidisciplinary; Phosphorylation; Protein kinase C; Protein Kinase C-epsilon - metabolism; Recombinant Proteins; Science; Science (multidisciplinary); Signal Transduction - physiology; Sister chromatids; Substrate specificity; Substrates; Switches
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-15163-6

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.