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

ABSTRACT: The Aurora B abscission checkpoint delays cytokinesis until resolution of DNA trapped in the cleavage furrow. This process involves PKC? phosphorylation of Aurora B S227. Assessing if this PKC?-Aurora B module provides a more widely exploited genome-protective control for the cell cycle, we show Aurora B phosphorylation at S227 by PKC? also occurs during mitosis. Expression of Aurora B S227A phenocopies inhibition of PKC? 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 PKC? activation following cell cycle dependent cleavage by caspase 7; knock-down of caspase 7 phenocopies PKC? loss, in a manner rescued by ectopically expressing/generating a free PKC? catalytic domain. Molecular dynamics indicates that Aurora B S227 phosphorylation induces conformational changes and this manifests in a profound switch in specificity towards S29 TopoII? phosphorylation, a response necessary for catenation resolution during mitosis.

SUBMITTER: Kelly JR

PROVIDER: S-EPMC7070073 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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

Kelly Joanna R JR Martini Silvia S Brownlow Nicola N Joshi Dhira D Federico Stefania S Jamshidi Shirin S Kjaer Svend S Lockwood Nicola N Rahman Khondaker Miraz KM Fraternali Franca F Parker Peter J PJ Soliman Tanya N TN

Nature communications 20200313 1

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 associate ...[more]

PMID: 32170202

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Project description:Aurora B kinase is an essential regulator of chromosome segregation with the action well characterized in eukaryotes. It is also implicated in cytokinesis, but the detailed mechanism remains less clear, partly due to the difficulty in separating the latter from the former function in a growing cell. A chemical genetic approach with an inhibitor of the enzyme added to a synchronized cell population at different stages of the cell cycle would probably solve this problem. In the deeply branched parasitic protozoan Trypanosoma brucei, an Aurora B homolog, TbAUK1, was found to control both chromosome segregation and cytokinetic initiation by evidence from RNAi and dominant negative mutation. To clearly separate these two functions, VX-680, an inhibitor of TbAUK1, was added to a synchronized T. brucei procyclic cell population at different cell cycle stages. The unique trans-localization pattern of the chromosomal passenger complex (CPC), consisting of TbAUK1 and two novel proteins TbCPC1 and TbCPC2, was monitored during mitosis and cytokinesis by following the migration of the proteins tagged with enhanced yellow fluorescence protein in live cells with time-lapse video microscopy. Inhibition of TbAUK1 function in S-phase, prophase or metaphase invariably arrests the cells in the metaphase, suggesting an action of TbAUK1 in promoting metaphase-anaphase transition. TbAUK1 inhibition in anaphase does not affect mitotic exit, but prevents trans-localization of the CPC from the spindle midzone to the anterior tip of the new flagellum attachment zone for cytokinetic initiation. The CPC in the midzone is dispersed back to the two segregated nuclei, while cytokinesis is inhibited. In and beyond telophase, TbAUK1 inhibition has no effect on the progression of cytokinesis or the subsequent G1, S and G2 phases until a new metaphase is attained. There are thus two clearly distinct points of TbAUK1 action in T. brucei: the metaphase-anaphase transition and cytokinetic initiation. This is the first time to our knowledge that the dual functions of an Aurora B homolog is dissected and separated into two clearly distinct time frames in a cell cycle.

Dataset Information

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

Publications

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

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