Human chromosome segregation involves multi-layered regulation of separase by the peptidyl-prolyl-isomerase Pin 1

Journal article

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.

Authors: Hellmuth, S; Rata, S; Brown, A; Heidmann, S; Novak, B

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Elsevier
• Journal: Molecular Cell
• Volume: 58
• Issue: 3
• Pages: 495-506
• Publication date: 2015-04-01
• DOI: 10.1016/j.molcel.2015.03.025
• EISSN: 1097-4164
• ISSN: 1097-2765