Human Chromosome Segregation Involves Multi-Layered Regulation of Separase by the Peptidyl-Prolyl-Isomerase Pin1

Titelangaben

Hellmuth, Susanne ; Rata, Scott ; Brown, Andreas ; Heidmann, Stefan ; Novak, Bela ; Stemmann, Olaf:
Human Chromosome Segregation Involves Multi-Layered Regulation of Separase by the Peptidyl-Prolyl-Isomerase Pin1.
In: Molecular Cell. Bd. 58 (2015) Heft 3 . - S. 495-506.
ISSN 1097-4164
DOI: https://doi.org/10.1016/j.molcel.2015.03.025

Angaben zu Projekten

Abstract

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.