Sister-chromatid separation is triggered by a speci¢c proteolytic cleavage of chromosomal cohesins catalyzed by the endopeptidase separase. Prior to anaphase, separase is inhibited independently by a⁄nity binding to securin and by speci¢c inhibitory phosphorylation. Here we show that separase itself is also subjected to proteolytic cleavages at three adjacent sites. The cleavages are auto-catalyzed and occur speci¢cally at anaphase coincident with separase activation. The cleaved fragments remain associated with each other and are catalytically active. Mapping of the cleavage sites reveals that all three sites are conserved in vertebrates underlining a signi¢cant function for this regulation. ß 2002 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies.

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