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      Human securin proteolysis is controlled by the spindle checkpoint and reveals when the APC/C switches from activation by Cdc20 to Cdh1

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          Abstract

          Progress through mitosis is controlled by the sequential destruction of key regulators including the mitotic cyclins and securin, an inhibitor of anaphase whose destruction is required for sister chromatid separation. Here we have used live cell imaging to determine the exact time when human securin is degraded in mitosis. We show that the timing of securin destruction is set by the spindle checkpoint; securin destruction begins at metaphase once the checkpoint is satisfied. Furthermore, reimposing the checkpoint rapidly inactivates securin destruction. Thus, securin and cyclin B1 destruction have very similar properties. Moreover, we find that both cyclin B1 and securin have to be degraded before sister chromatids can separate. A mutant form of securin that lacks its destruction box (D-box) is still degraded in mitosis, but now this is in anaphase. This destruction requires a KEN box in the NH 2 terminus of securin and may indicate the time in mitosis when ubiquitination switches from APC Cdc20 to APC Cdh1. Lastly, a D-box mutant of securin that cannot be degraded in metaphase inhibits sister chromatid separation, generating a cut phenotype where one cell can inherit both copies of the genome. Thus, defects in securin destruction alter chromosome segregation and may be relevant to the development of aneuploidy in cancer.

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          Sister-chromatid separation at anaphase onset is promoted by cleavage of the cohesin subunit Scc1.

          Cohesion between sister chromatids is established during DNA replication and depends on a multiprotein complex called cohesin. Attachment of sister kinetochores to the mitotic spindle during mitosis generates forces that would immediately split sister chromatids were it not opposed by cohesion. Cohesion is essential for the alignment of chromosomes in metaphase but must be abolished for sister separation to start during anaphase. In the budding yeast Saccharomyces cerevisiae, loss of sister-chromatid cohesion depends on a separating protein (separin) called Esp1 and is accompanied by dissociation from the chromosomes of the cohesion subunit Scc1. Here we show that Esp1 causes the dissociation of Scc1 from chromosomes by stimulating its cleavage by proteolysis. A mutant Scc1 is described that is resistant to Esp1-dependent cleavage and which blocks both sister-chromatid separation and the dissociation of Scc1 from chromosomes. The evolutionary conservation of separins indicates that the proteolytic cleavage of cohesion proteins might be a general mechanism for triggering anaphase.
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            Cleavage of cohesin by the CD clan protease separin triggers anaphase in yeast.

            In eukaryotic cells, replicated DNA strands remain physically connected until their segregation to opposite poles of the cell during anaphase. This "sister chromatid cohesion" is essential for the alignment of chromosomes on the mitotic spindle during metaphase. Cohesion depends on the multisubunit cohesin complex, which possibly forms the physical bridges connecting sisters. Proteolytic cleavage of cohesin's Sccl subunit at the metaphase to anaphase transition is essential for sister chromatid separation and depends on a conserved protein called separin. We show here that separin is a cysteine protease related to caspases that alone can cleave Sccl in vitro. Cleavage of Sccl in metaphase arrested cells is sufficient to trigger the separation of sister chromatids and their segregation to opposite cell poles.
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              The phosphatase Cdc14 triggers mitotic exit by reversal of Cdk-dependent phosphorylation.

              Exit from mitosis requires the inactivation of mitotic cyclin-dependent kinases (CDKs) by an unknown mechanism. We show that the Cdc14 phosphatase triggers mitotic exit by three parallel mechanisms, each of which inhibits Cdk activity. Cdc14 dephosphorylates Sic1, a Cdk inhibitor, and Swi5, a transcription factor for SIC1, and induces degradation of mitotic cyclins, likely by dephosphorylating the activator of mitotic cyclin degradation, Cdh1/Hct1. Feedback between these pathways may lead to precipitous collapse of mitotic CDK activity and help coordinate exit from mitosis.
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                Author and article information

                Journal
                J Cell Biol
                The Journal of Cell Biology
                The Rockefeller University Press
                0021-9525
                1540-8140
                24 June 2002
                : 157
                : 7
                : 1125-1137
                Affiliations
                [1 ]Wellcome/Cancer Research UK Institute, Cambridge CB2 1QR, United Kingdom
                [2 ]Research Institute of Molecular Pathology, A-1030 Vienna, Austria
                Author notes

                Address correspondence to Jonathon Pines, Wellcome/Cancer Research UK Institute, Tennis Court Rd., Cambridge CB2 1QR, UK. Tel.: 44-1223-334096. Fax: 44-1223-334089. E-mail: j.pines@ 123456welc.cam.ac.uk

                Article
                0111001
                10.1083/jcb.200111001
                2173548
                12070128
                99f8f1a9-3a5f-4fce-a5ac-f26a3a41cae1
                Copyright © 2002, The Rockefeller University Press
                History
                : 1 November 2001
                : 11 April 2002
                : 10 May 2002
                Categories
                Article

                Cell biology
                separase; proteolysis; mitosis; chromosome; ubiquitin
                Cell biology
                separase; proteolysis; mitosis; chromosome; ubiquitin

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