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      Sds22 and Repo-Man stabilize chromosome segregation by counteracting Aurora B on anaphase kinetochores

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          Abstract

          Repo-Man and Sds22 counteract Aurora B phosphorylation of Dsn1 and thus regulate the kinetochore–microtubule interface during anaphase.

          Abstract

          During mitotic spindle assembly, Aurora B kinase is part of an error correction mechanism that detaches microtubules from kinetochores that are under low mechanical tension. During anaphase, however, kinetochore–microtubule attachments must be maintained despite a drop of tension after removal of sister chromatid cohesion. Consistent with this requirement, Aurora B relocates away from chromosomes to the central spindle at the metaphase–anaphase transition. By ribonucleic acid interference screening using a phosphorylation biosensor, we identified two PP1-targeting subunits, Sds22 and Repo-Man, which counteracted Aurora B–dependent phosphorylation of the outer kinetochore component Dsn1 during anaphase. Sds22 or Repo-Man depletion induced transient pauses during poleward chromosome movement and a high incidence of chromosome missegregation. Thus, our study identifies PP1-targeting subunits that regulate the microtubule–kinetochore interface during anaphase for faithful chromosome segregation.

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          The spindle-assembly checkpoint in space and time.

          In eukaryotes, the spindle-assembly checkpoint (SAC) is a ubiquitous safety device that ensures the fidelity of chromosome segregation in mitosis. The SAC prevents chromosome mis-segregation and aneuploidy, and its dysfunction is implicated in tumorigenesis. Recent molecular analyses have begun to shed light on the complex interaction of the checkpoint proteins with kinetochores--structures that mediate the binding of spindle microtubules to chromosomes in mitosis. These studies are finally starting to reveal the mechanisms of checkpoint activation and silencing during mitotic progression.
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            The small molecule Hesperadin reveals a role for Aurora B in correcting kinetochore–microtubule attachment and in maintaining the spindle assembly checkpoint

            The proper segregation of sister chromatids in mitosis depends on bipolar attachment of all chromosomes to the mitotic spindle. We have identified the small molecule Hesperadin as an inhibitor of chromosome alignment and segregation. Our data imply that Hesperadin causes this phenotype by inhibiting the function of the mitotic kinase Aurora B. Mammalian cells treated with Hesperadin enter anaphase in the presence of numerous monooriented chromosomes, many of which may have both sister kinetochores attached to one spindle pole (syntelic attachment). Hesperadin also causes cells arrested by taxol or monastrol to enter anaphase within <1 h, whereas cells in nocodazole stay arrested for 3–5 h. Together, our data suggest that Aurora B is required to generate unattached kinetochores on monooriented chromosomes, which in turn could promote bipolar attachment as well as maintain checkpoint signaling.
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              Chromosomal passengers: conducting cell division.

              Mitosis and meiosis are remarkable processes during which cells undergo profound changes in their structure and physiology. These events are orchestrated with a precision that is worthy of a classical symphony, with different activities being switched on and off at precise times and locations throughout the cell. One essential 'conductor' of this symphony is the chromosomal passenger complex (CPC), which comprises Aurora-B protein kinase, the inner centromere protein INCENP, survivin and borealin (also known as Dasra-B). Studies of the CPC are providing insights into its functions, which range from chromosome-microtubule interactions to sister chromatid cohesion to cytokinesis, and constitute one of the most dynamic areas of ongoing mitosis and meiosis research.
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                Author and article information

                Journal
                J Cell Biol
                J. Cell Biol
                jcb
                The Journal of Cell Biology
                The Rockefeller University Press
                0021-9525
                1540-8140
                23 July 2012
                : 198
                : 2
                : 173-183
                Affiliations
                [1 ]Institute of Biochemistry, Swiss Federal Institute of Technology Zurich, CH-8093 Zurich, Switzerland
                [2 ]Department of Biology, University of Pennsylvania, Philadelphia, PA 19104
                [3 ]Max Planck Institute for Molecular Cell Biology and Genetics, D-01307 Dresden, Germany
                Author notes
                Correspondence to Daniel W. Gerlich: daniel.gerlich@ 123456imba.oeaw.ac.at

                D.W. Gerlich’s present address is Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria.

                Article
                201112112
                10.1083/jcb.201112112
                3410419
                22801782
                c6f97642-d3e6-417f-b2ab-907ada997deb
                © 2012 Wurzenberger et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

                History
                : 20 December 2011
                : 13 June 2012
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                Cell biology
                Cell biology

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