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Published online 17 June 2002. doi:10.1083/jcb.200111001
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© The Rockefeller University Press, 0021-9525/2002/6/1125 $5.00
The Journal of Cell Biology, Volume 157, Number 7, June 24, 2002 1125-1137

Article

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



Anja Hagting1, Nicole den Elzen1, Hartmut C. Vodermaier2, Irene C. Waizenegger2, Jan-Michael Peters2 and Jonathon Pines1

1 Wellcome/Cancer Research UK Institute, Cambridge CB2 1QR, United Kingdom
2 Research Institute of Molecular Pathology, A-1030 Vienna, Austria

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{at}welc.cam.ac.uk

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 NH2 terminus of securin and may indicate the time in mitosis when ubiquitination switches from APCCdc20 to APCCdh1. 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.

Key Words: separase; proteolysis; mitosis; chromosome; ubiquitin


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