Human chromosome segregation involves multi-layered regulation of separase by the peptidyl-prolyl-isomerase Pin1.
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.
Chair of Genetics, University of Bayreuth, Universitätsstraße 30, 95440 Bayreuth, Germany.
Susanne
S
Hellmuth
Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
Scott
S
Rata
Chair of Genetics, University of Bayreuth, Universitätsstraße 30, 95440 Bayreuth, Germany.
Andreas
A
Brown
Chair of Genetics, University of Bayreuth, Universitätsstraße 30, 95440 Bayreuth, Germany.
Stefan
S
Heidmann
Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
Bela
B
Novak
Chair of Genetics, University of Bayreuth, Universitätsstraße 30, 95440 Bayreuth, Germany. Electronic address: olaf.stemmann@uni-bayreuth.de.
Olaf
O
Stemmann
D000705:Anaphase / Q000235:genetics; D016203:CDC2 Protein Kinase; D002842:Chromatids / Q000235:genetics; D020090:Chromosome Segregation / Q000235:genetics*; D056744:Cyclin B1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D008677:Metaphase / Q000235:genetics; D008856:Microscopy, Fluorescence; D008938:Mitosis / Q000235:genetics; D008957:Models, Genetic; D008958:Models, Molecular; D009154:Mutation; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D034622:RNA Interference; D064249:Securin / Q000235:genetics / Q000378:metabolism; D064247:Separase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
D056744:Cyclin B1; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D064249:Securin; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases; C577987:ESPL1 protein, human; D064247:Separase; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase