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

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          Abstract

          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.

          Abstract

          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.

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          Most cited references 27

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          Many cuts to ruin: a comprehensive update of caspase substrates

          Apoptotic cell death is executed by the caspase-mediated cleavage of various vital proteins. Elucidating the consequences of this endoproteolytic cleavage is crucial for our understanding of cell death and other biological processes. Many caspase substrates are just cleaved as bystanders, because they happen to contain a caspase cleavage site in their sequence. Several targets, however, have a discrete function in propagation of the cell death process. Many structural and regulatory proteins are inactivated by caspases, while other substrates can be activated. In most cases, the consequences of this gain-of-function are poorly understood. Caspase substrates can regulate the key morphological changes in apoptosis. Several caspase substrates also act as transducers and amplifiers that determine the apoptotic threshold and cell fate. This review summarizes the known caspase substrates comprising a bewildering list of more than 280 different proteins. We highlight some recent aspects inferred by the cleavage of certain proteins in apoptosis. We also discuss emerging themes of caspase cleavage in other forms of cell death and, in particular, in apparently unrelated processes, such as cell cycle regulation and cellular differentiation.
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            ESCRT-III governs the Aurora B-mediated abscission checkpoint through CHMP4C.

            The endosomal sorting complex required for transport (ESCRT) machinery plays an evolutionarily conserved role in cytokinetic abscission, the final step of cell division where daughter cells are physically separated. Here, we show that charged multivesicular body (MVB) protein 4C (CHMP4C), a human ESCRT-III subunit, is involved in abscission timing. This function correlated with its differential spatiotemporal distribution during late stages of cytokinesis. Accordingly, CHMP4C functioned in the Aurora B-dependent abscission checkpoint to prevent both premature resolution of intercellular chromosome bridges and accumulation of DNA damage. CHMP4C engaged the chromosomal passenger complex (CPC) via interaction with Borealin, which suggested a model whereby CHMP4C inhibits abscission upon phosphorylation by Aurora B. Thus, the ESCRT machinery may protect against genetic damage by coordinating midbody resolution with the abscission checkpoint.
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              The chromosomal passenger complex controls the function of endosomal sorting complex required for transport-III Snf7 proteins during cytokinesis

              Summary Cytokinesis controls the proper segregation of nuclear and cytoplasmic materials at the end of cell division. The chromosomal passenger complex (CPC) has been proposed to monitor the final separation of the two daughter cells at the end of cytokinesis in order to prevent cell abscission in the presence of DNA at the cleavage site, but the precise molecular basis for this is unclear. Recent studies indicate that abscission could be mediated by the assembly of filaments comprising components of the endosomal sorting complex required for transport-III (ESCRT-III). Here, we show that the CPC subunit Borealin interacts directly with the Snf7 components of ESCRT-III in both Drosophila and human cells. Moreover, we find that the CPC's catalytic subunit, Aurora B kinase, phosphorylates one of the three human Snf7 paralogues—CHMP4C—in its C-terminal tail, a region known to regulate its ability to form polymers and associate with membranes. Phosphorylation at these sites appears essential for CHMP4C function because their mutation leads to cytokinesis defects. We propose that CPC controls abscission timing through inhibition of ESCRT-III Snf7 polymerization and membrane association using two concurrent mechanisms: interaction of its Borealin component with Snf7 proteins and phosphorylation of CHMP4C by Aurora B.
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                Author and article information

                Contributors
                peter.parker@crick.ac.uk
                t.soliman@qmul.ac.uk
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                13 March 2020
                13 March 2020
                2020
                : 11
                Affiliations
                [1 ]ISNI 0000 0004 1795 1830, GRID grid.451388.3, Protein Phosphorylation Laboratory, , Francis Crick Institute, ; 1 Midland Rd, London, NW1 1AT UK
                [2 ]ISNI 0000 0004 1795 1830, GRID grid.451388.3, Peptide Chemistry Platform, , Francis Crick Institute, ; 1 Midland Rd, London, NW1 1AT UK
                [3 ]ISNI 0000 0001 2322 6764, GRID grid.13097.3c, School of Cancer and Pharmaceutical Sciences, , King’s College London, ; London, UK
                [4 ]ISNI 0000 0004 1795 1830, GRID grid.451388.3, Structural Biology Platform, , Francis Crick Institute, ; 1 Midland Rd, London, NW1 1AT UK
                [5 ]ISNI 0000 0001 2322 6764, GRID grid.13097.3c, Randall Centre for Cell and Molecular Biophysics, , King’s College London, ; London, UK
                [6 ]ISNI 0000000121662407, GRID grid.5379.8, Present Address: Cancer Research UK, Manchester Institute, ; Alderley Park, SK10 4TG UK
                [7 ]ISNI 0000 0004 1759 6875, GRID grid.466805.9, Present Address: Instituto de Neurociencias, ; Av. Santiago Ramón y Cajal s/n 03550, San Juan de Alicante, Spain
                [8 ]ISNI 0000 0001 2171 1133, GRID grid.4868.2, Present Address: Barts Cancer Institute, Queen Mary University London, ; Charterhouse Square, London, EC1M 6BE UK
                Article
                15163
                10.1038/s41467-020-15163-6
                7070073
                32170202
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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                kinases, mitosis, cell signalling, phosphorylation

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