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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.

Original publication

DOI

10.1083/jcb.200506119

Type

Journal article

Journal

J Cell Biol

Publication Date

13/03/2006

Volume

172

Pages

847 - 860

Keywords

Anaphase, Animals, Carrier Proteins, Cell Cycle, Cell Cycle Proteins, Cell Line, Chromosomal Proteins, Non-Histone, Chromosome Segregation, DNA Replication Timing, Embryonic Development, Endopeptidases, Female, Fibroblasts, Genes, Lethal, Hematopoietic Stem Cells, Hepatocytes, Liver Regeneration, Male, Mice, Mice, Knockout, Mitosis, Nuclear Proteins, Polyploidy, Securin, Separase