title: Nuclear exclusion of separase prevents cohesin cleavage in interphase cells.
abstract: During mitosis, equal transmission of the duplicated chromosomes demands a strict regulation of separase, which cleaves cohesin and triggers sister chromatid separation in anaphase. Vertebrate separase is inhibited by securin and the inhibitory phosphorylation of separase. However, knockout experiments indicate that securin is dispensable and the inhibitory phosphorylation was observed only in M phase cells. This begs the question how cohesin cleavage by separase is prevented in the absence these two mechanisms. Here we show that separase is excluded from cohesin by the nuclear envelope, which forms in telophase and disassembles in mitosis. The exclusion is achieved passively by its large physical mass and may be backed up by the CRM1-dependent nuclear export. A functional NES motif is identified in separase. We demonstrated that the nuclear envelope is sufficient to prevent active separase from cleaving nuclear cohesin. We propose that the nuclear exclusion is important to prevent cohesin cleavage during interphase in the absence of securin and the phosphorylation inhibition.
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9148, USA.
authors.forename: Yuxiao
authors.initials: Y
authors.lastname: Sun
authors.forename: Hong
authors.initials: H
authors.lastname: Yu
authors.forename: Hui
authors.initials: H
authors.lastname: Zou
mesh_terms: D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D000705:Anaphase; D018797:Cell Cycle Proteins / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism*; D002868:Chromosomal Proteins, Non-Histone / Q000502:physiology*; D020090:Chromosome Segregation; D010450:Endopeptidases / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D007399:Interphase; D028884:Karyopherins / Q000378:metabolism; D008938:Mitosis; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000502:physiology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D064249:Securin; D064247:Separase; D017386:Sequence Homology, Amino Acid; D000097606:Exportin 1 Protein; D000097722:Cohesins
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D010450:Endopeptidases; D028884:Karyopherins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D064249:Securin; D064247:Separase; D000097606:Exportin 1 Protein; D000097722:Cohesins; C578002:pituitary tumor-transforming protein 1, human; C577987:ESPL1 protein, human