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Ring-shaped cohesin keeps sister chromatids paired until cleavage of its Scc1/Rad21 subunit by separase triggers chromosome segregation in anaphase. Vertebrate separase is held inactive by mutually exclusive binding to securin or Cdk1-cyclin B1 and becomes unleashed only upon ubiquitin-dependent degradation of these regulators. Although most separase is usually found in association with securin, this anaphase inhibitor is dispensable for murine life while Cdk1-cyclin B1-dependent control of separase is essential. Here, we show that securin-independent inhibition of separase by Cdk1-cyclin B1 in early mitosis requires the phosphorylation-specific peptidyl-prolyl cis/trans isomerase Pin1. Furthermore, isomerization of previously securin-bound separase at the metaphase-to-anaphase transition renders it resistant to re-inhibition by residual securin. At the same time, isomerization also limits the half-life of separase's proteolytic activity, explaining how cohesin can be reloaded onto telophase chromatin in the absence of securin and cyclin B1 without being cleaved.

Original publication

DOI

10.1016/j.molcel.2015.03.025

Type

Journal article

Journal

Mol Cell

Publication Date

07/05/2015

Volume

58

Pages

495 - 506

Keywords

Anaphase, CDC2 Protein Kinase, Chromatids, Chromosome Segregation, Cyclin B1, Cyclin-Dependent Kinases, Gene Expression Regulation, Enzymologic, HEK293 Cells, Humans, Immunoblotting, Metaphase, Microscopy, Fluorescence, Mitosis, Models, Genetic, Models, Molecular, Mutation, NIMA-Interacting Peptidylprolyl Isomerase, Peptidylprolyl Isomerase, Protein Binding, Protein Conformation, RNA Interference, Securin, Separase