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Published 13 March 2006. doi:10.1083/jcb.200506119
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 172, Number 6, 847-860
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Article

 Separase: a universal trigger for sister chromatid disjunction but not chromosome cycle progression

Karin G. Wirth1,2, Gordana Wutz1, Nobuaki R. Kudo1, Chantal Desdouets3, Anders Zetterberg4, Shahryar Taghybeeglu1, Janina Seznec2, Germain M. Ducos3, Romeo Ricci1,5, Nicole Firnberg1, Jan-Michael Peters1, and Kim Nasmyth1

1 Research Institute of Molecular Pathology, A-1030 Vienna, Austria
2 Klinik und Poliklinik für Innere Medizin II, Klinikum der Friedrich-Schiller-Universität Jena, 07740 Jena, Germany
3 Département Génétique, Développement et Pathologie Moléculaire, Institut Cochin, 75014 Paris, France
4 Division of Cellular and Molecular Tumor Cancer Center, Department of Oncology and Pathology, Karolinska Institute, 17177 Stockholm, Sweden
5 Eidgenössische Technische Hochschule Zürich, Institute of Cell Biology, 8093 Zürich, Switzerland

Correspondence to Kim Nasmyth: kim.nasmyth{at}bioch.ox.ac.uk; or Jan-Michael Peters: peters{at}imp.univie.ac.at

Separase is a protease whose liberation from its inhibitory chaperone Securin triggers sister chromatid disjunction at anaphase onset in yeast by cleaving cohesin's kleisin subunit. We have created conditional knockout alleles of the mouse Separase and Securin genes. Deletion of both copies of Separase but not Securin causes embryonic lethality. Loss of Securin reduces Separase activity because deletion of just one copy of the Separase gene is lethal to embryos lacking Securin. In embryonic fibroblasts, Separase depletion blocks sister chromatid separation but does not prevent other aspects of mitosis, cytokinesis, or chromosome replication. Thus, fibroblasts lacking Separase become highly polyploid. Hepatocytes stimulated to proliferate in vivo by hepatectomy also become unusually large and polyploid in the absence of Separase but are able to regenerate functional livers. Separase depletion in bone marrow causes aplasia and the presumed death of hematopoietic cells other than erythrocytes. Destruction of sister chromatid cohesion by Separase may be a universal feature of mitosis in eukaryotic cells.

K.G. Wirth and G. Wutz contributed equally to this paper.

K. Nasmyth's present address is University of Oxford, Oxford OX1 2JD, England.

Abbreviations used in this paper: AdCre, adenovirus expressing Cre recombinase; AdGFP, adenovirus expressing GFP; APC/C, anaphase promoting complex or cyclosome; BAC, bacterial artificial chromosome; CREST, calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia; dpc, days post coitus; ES, embryonic stem; iMEF: immortalized MEF; MEF, mouse embryonic fibroblast; P-H3, phosphorylated histone H3; pI/C, poly(I)poly(C).


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