464 results match your criteria separase

The Cyclin B2/CDK1 Complex Conservatively Inhibits Separase Activity in Oocyte Meiosis II.

Front Cell Dev Biol 2021 11;9:648053. Epub 2021 Mar 11.

Department of Reproductive Medicine, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, China.

Recently, we have reported that the cyclin B2/CDK1 complex regulates homologous chromosome segregation through inhibiting separase activity in oocyte meiosis I, which further elucidates the compensation of cyclin B2 on cyclin B1's function in meiosis I. However, whether cyclin B2/CDK1 complex also negatively regulates separase activity during oocyte meiosis II remains unknown. In the present study, we investigated the function of cyclin B2 in meiosis II of oocyte. Read More

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Deprotection of centromeric cohesin at meiosis II requires APC/C activity but not kinetochore tension.

EMBO J 2021 Apr 1;40(7):e106812. Epub 2021 Mar 1.

Laboratory of Chromosome Biology, Max Planck Institute of Biochemistry, Martinsried, Germany.

Genome haploidization involves sequential loss of cohesin from chromosome arms and centromeres during two meiotic divisions. At centromeres, cohesin's Rec8 subunit is protected from separase cleavage at meiosis I and then deprotected to allow its cleavage at meiosis II. Protection of centromeric cohesin by shugoshin-PP2A seems evolutionarily conserved. Read More

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Kinetochore individualization in meiosis I is required for centromeric cohesin removal in meiosis II.

EMBO J 2021 Apr 1;40(7):e106797. Epub 2021 Mar 1.

Institut de Biologie Paris Seine, Sorbonne Université, Paris, France.

Partitioning of the genome in meiosis occurs through two highly specialized cell divisions, named meiosis I and meiosis II. Step-wise cohesin removal is required for chromosome segregation in meiosis I, and sister chromatid segregation in meiosis II. In meiosis I, mono-oriented sister kinetochores appear as fused together when examined by high-resolution confocal microscopy, whereas they are clearly separated in meiosis II, when attachments are bipolar. Read More

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Prolonged mitosis causes separase deregulation and chromosome nondisjunction.

Cell Rep 2021 Jan;34(3):108652

Division of Experimental Pathology, Cancer Institute of the Japanese Foundation for Cancer Research (JFCR), Ariake 3-8-31 Koto-ku, 135-8550 Tokyo, Japan. Electronic address:

During mitotic chromosome segregation, the protease separase severs cohesin between sister chromatids. A probe for separase activity has shown that separase undergoes abrupt activation shortly before anaphase onset, after being suppressed throughout metaphase; however, the relevance of this control remains unclear. Here, we report that separase activates precociously, with respect to anaphase onset, during prolonged metaphase in multiple types of cancer cell lines. Read More

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January 2021

Structure and Function of the Separase-Securin Complex.

Subcell Biochem 2021 ;96:217-232

Department of Biological Sciences, Columbia University, New York, NY, 10027, USA.

Separase is a large cysteine protease in eukaryotes and has crucial roles in many cellular processes, especially chromosome segregation during mitosis and meiosis, apoptosis, DNA damage repair, centrosome disengagement and duplication, spindle stabilization and elongation. It dissolves the cohesion between sister chromatids by cleaving one of the subunits of the cohesin ring for chromosome segregation. The activity of separase is tightly controlled at many levels, through direct binding of inhibitory proteins as well as posttranslational modification. Read More

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February 2021

How noncrossover homologs are conjoined and segregated in Drosophila male meiosis I: Stable but reversible homolog linkers require a novel Separase target protein.

PLoS Genet 2020 10 1;16(10):e1008997. Epub 2020 Oct 1.

Department of Biochemistry, Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee, United States of America.

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October 2020

Chromosome separation during Drosophila male meiosis I requires separase-mediated cleavage of the homolog conjunction protein UNO.

PLoS Genet 2020 10 1;16(10):e1008928. Epub 2020 Oct 1.

Department of Molecular Life Science (DMLS), University of Zurich, Zurich, Switzerland.

Regular chromosome segregation during the first meiotic division requires prior pairing of homologous chromosomes into bivalents. During canonical meiosis, linkage between homologous chromosomes is maintained until late metaphase I by chiasmata resulting from meiotic recombination in combination with distal sister chromatid cohesion. Separase-mediated elimination of cohesin from chromosome arms at the end of metaphase I permits terminalization of chiasmata and homolog segregation to opposite spindle poles during anaphase I. Read More

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October 2020

Haploinsufficiency of cohesin protease, Separase, promotes regeneration of hematopoietic stem cells in mice.

Stem Cells 2020 Sep 30. Epub 2020 Sep 30.

Texas Childrens Cancer Center, Baylor College of Medicine, Houston, Texas, USA.

Cohesin recently emerged as a new regulator of hematopoiesis and leukemia. In addition to cohesin, whether proteins that regulate cohesin's function have any direct role in hematopoiesis and hematologic diseases have not been fully examined. Separase, encoded by the ESPL1 gene, is an important regulator of cohesin's function. Read More

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September 2020

PP2A dephosphorylates Pds1 and inhibits spindle elongation in .

J Cell Sci 2020 07 29;133(14). Epub 2020 Jul 29.

Biology Department, Brooklyn College, The City University of New York, Brooklyn, NY 11238, USA

PP2A (the form of protein phosphatase 2A containing Cdc55) regulates cell cycle progression by reversing cyclin-dependent kinase (CDK)- and polo-like kinase (Cdc5)-dependent phosphorylation events. In , Cdk1 phosphorylates securin (Pds1), which facilitates Pds1 binding and inhibits separase (Esp1). During anaphase, Esp1 cleaves the cohesin subunit Scc1 and promotes spindle elongation. Read More

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A prognostic model based on cell-cycle control predicts outcome of breast cancer patients.

BMC Cancer 2020 Jun 16;20(1):558. Epub 2020 Jun 16.

Institute of Biomedicine, University of Turku, Turku, Finland.

Background: A prognostic model combining biomarkers of metaphase-anaphase transition of the cell cycle was developed for invasive breast cancer. The prognostic value and clinical applicability of the model was evaluated in comparison with the routine prognosticators of invasive breast carcinoma.

Methods: The study comprised 1135 breast cancer patients with complete clinical data and up to 22-year follow-up. Read More

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Centrosome reduction in newly-generated tetraploid cancer cells obtained by separase depletion.

Sci Rep 2020 06 4;10(1):9152. Epub 2020 Jun 4.

Gastrointestinal and Pancreatic Oncology Team, Institut D'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, 08036, Spain.

Tetraploidy, a common feature in cancer, results in the presence of extra centrosomes, which has been associated with chromosome instability (CIN) and aneuploidy. Deregulation in the number of centrosomes triggers tumorigenesis. However, how supernumerary centrosomes evolve during the emergence of tetraploid cells remains yet to be elucidated. Read More

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Dun1, a Chk2-related kinase, is the central regulator of securin-separase dynamics during DNA damage signaling.

Nucleic Acids Res 2020 06;48(11):6092-6107

Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Proteos, 61 Biopolis Drive, Singapore.

The DNA damage checkpoint halts cell cycle progression in G2 in response to genotoxic insults. Central to the execution of cell cycle arrest is the checkpoint-induced stabilization of securin-separase complex (yeast Pds1-Esp1). The checkpoint kinases Chk1 and Chk2 (yeast Chk1 and Rad53) are thought to critically contribute to the stability of securin-separase complex by phosphorylation of securin, rendering it resistant to proteolytic destruction by the anaphase promoting complex (APC). Read More

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Cyclin A1 in Oocytes Prevents Chromosome Segregation And Anaphase Entry.

Sci Rep 2020 05 4;10(1):7455. Epub 2020 May 4.

Central European Institute of Technology, Department of Genetics and Reproduction, Veterinary Research Institute, Brno, Czech Republic.

In several species, including Xenopus, mouse and human, two members of cyclin A family were identified. Cyclin A2, which is ubiquitously expressed in dividing cells and plays role in DNA replication, entry into mitosis and spindle assembly, and cyclin A1, whose function is less clear and which is expressed in spermatocytes, leukemia cells and in postmitotic multiciliated cells. Deletion of the gene showed that cyclin A1 is essential for male meiosis, but nonessential for female meiosis. Read More

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Wapl releases Scc1-cohesin and regulates chromosome structure and segregation in mouse oocytes.

J Cell Biol 2020 04;219(4)

Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna BioCenter, Vienna, Austria.

Cohesin is essential for genome folding and inheritance. In somatic cells, these functions are both mediated by Scc1-cohesin, which in mitosis is released from chromosomes by Wapl and separase. In mammalian oocytes, cohesion is mediated by Rec8-cohesin. Read More

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Securin-independent regulation of separase by checkpoint-induced shugoshin-MAD2.

Nature 2020 04 8;580(7804):536-541. Epub 2020 Apr 8.

Chair of Genetics, University of Bayreuth, Bayreuth, Germany.

Separation of eukaryotic sister chromatids during the cell cycle is timed by the spindle assembly checkpoint (SAC) and ultimately triggered when separase cleaves cohesion-mediating cohesin. Silencing of the SAC during metaphase activates the ubiquitin ligase APC/C (anaphase-promoting complex, also known as the cyclosome) and results in the proteasomal destruction of the separase inhibitor securin. In the absence of securin, mammalian chromosomes still segregate on schedule, but it is unclear how separase is regulated under these conditions. Read More

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Separase-triggered apoptosis enforces minimal length of mitosis.

Nature 2020 04 8;580(7804):542-547. Epub 2020 Apr 8.

Chair of Genetics, University of Bayreuth, Bayreuth, Germany.

Prolonged mitosis often results in apoptosis. Shortened mitosis causes tumorigenic aneuploidy, but it is unclear whether it also activates the apoptotic machinery. Separase, a cysteine protease and trigger of all eukaryotic anaphases, has a caspase-like catalytic domain but has not previously been associated with cell death. Read More

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The cohesin release factor Wapl interacts with Bub3 to govern SAC activity in female meiosis I.

Sci Adv 2020 04 8;6(15):eaax3969. Epub 2020 Apr 8.

College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China.

During mitotic prophase, cohesins are removed from chromosome arms by Wapl to ensure faithful sister chromatid separation. However, during female meiosis I, the resolution of chiasmata requires the proteolytic cleavage of cohesin subunit Rec8 along chromosome arms by Separase to separate homologs, and thus the role of Wapl remained unknown. Here, we report that Wapl functions as a regulator of spindle assembly checkpoint (SAC) to prevent aneuploidy in meiosis I. Read More

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Intertwined Functions of Separase and Caspase in Cell Division and Programmed Cell Death.

Sci Rep 2020 04 9;10(1):6159. Epub 2020 Apr 9.

Department of Molecular, Cellular, and Developmental Biology, and Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA, 93106, USA.

Timely sister chromatid separation, promoted by separase, is essential for faithful chromosome segregation. Separase is a member of the CD clan of cysteine proteases, which also includes the pro-apoptotic enzymes known as caspases. We report a role for the C. Read More

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Separase activity distribution can be a marker of major molecular response and proliferation of CD34 cells in TKI-treated chronic myeloid leukemia patients.

Ann Hematol 2020 May 6;99(5):991-1006. Epub 2020 Apr 6.

Department of Hematology and Oncology, University Hospital Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Separase, a cysteine endopeptidase, is a key player in mitotic sister chromatid separation, replication fork dynamics, and DNA repair. Aberrant expression and/or altered separase proteolytic activity are associated with aneuploidy, tumorigenesis, and disease progression. Since genomic instability and clonal evolution are hallmarks of progressing chronic myeloid leukemia (CML), we have comparatively examined separase proteolytic activity in TKI-treated chronic phase CML. Read More

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Data set on Separase Inhibitor-Sepin-1 toxicity on organ weights, hematology and clinical parameters in Sprague-Dawley rats.

Data Brief 2020 Apr 22;29:105159. Epub 2020 Jan 22.

Texas Children's Cancer Center, Departments of Pediatrics and Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.

Separase Inhibitor-Sepin-1 has shown great promise as a developmental chemotherapeutic agent to treat Separase-overexpressing tumors, however, very little is known about its toxicity profile. Here we present the data set of organ weights, hematology, and clinical chemistry parameters in Sepin-1-treated Sprague-Dawley rats. The data set was generated from two study groups-Main Study and Recovery Study, with in-life duration of 29 and 57 days, respectively. Read More

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Overexpression of cyclin A1 promotes meiotic resumption but induces premature chromosome separation in mouse oocyte.

J Cell Physiol 2020 10 6;235(10):7136-7145. Epub 2020 Feb 6.

Department of Reproductive Medicine, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, China.

Mammalian cyclin A1 is prominently expressed in testis and essential for meiosis in the male mouse, however, it shows weak expression in ovary, especially during oocyte maturation. To understand why cyclin A1 behaves in this way in the oocyte, we investigated the effect of cyclin A1 overexpression on mouse oocyte meiotic maturation. Our results revealed that cyclin A1 overexpression triggered meiotic resumption even in the presence of germinal vesicle breakdown inhibitor, milrinone. Read More

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October 2020

Stability and pharmacokinetics of separase inhibitor-Sepin-1 in Sprague-Dawley rats.

Biochem Pharmacol 2020 04 10;174:113808. Epub 2020 Jan 10.

Texas Children's Cancer Center, Departments of Pediatrics and Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. Electronic address:

Separase, a sister chromatid cohesion-resolving enzyme, is an oncogene and overexpressed in many human cancers. Sepin-1 (2,2-dimethyl-5-nitro-2H-benzimidazole-1,3-dioxide) is a potent separase inhibitor that impedes cancer cell growth, cell migration, and wound healing, suggesting that Sepin-1 possesses a great potential to target separase-overexpressing tumors. As a part of the IND-enabling studies to bring Sepin-1 to clinic, herein we report the results from a 28-day repeat-dose pharmacokinetic study of Sepin-1 in rats. Read More

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High Rate of Detection of Human ESPL1-HBV S Fusion Gene in Patients With HBV-related Liver Cancer: A Chinese Case-Control Study.

Anticancer Res 2020 Jan;40(1):245-252

Department of Infectious Diseases, The First Affiliated Hospital of Guangxi Medical University, Nanning, P.R. China

Aim: It has been shown that the integration of hepatitis B virus (HBV) gene into the host genome is a high-risk factor for development of hepatocellular carcinoma (HCC). However, the relationship between HBV S-integrated human extra spindle pole bodies-like 1 (ESPL1) gene and HCC is unknown. This study was designed to detect HBV S-integrated human ESPL1 fusion gene in patients with HCC for potentially using this fusion gene as a biomarker for HCC diagnosis. Read More

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January 2020

Toxicity study of separase inhibitor-Sepin-1 in Sprague-Dawley rats.

Pathol Res Pract 2020 Jan 11;216(1):152730. Epub 2019 Nov 11.

Texas Children's Cancer Center, Departments of Pediatrics and Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. Electronic address:

Sepin-1 is a small compound that inhibits enzymatic activity of Separase and growth of cancer cells. As part of the IND-enabling studies to develop Sepin-1 as a chemotherapeutic agent, herein we have profiled the toxicity of Sepin-1 in Sprague-Dawley rats in a good laboratory practice (GLP) setting. The maximum tolerated dose (MTD) of Sepin-1 in rats is 40 mg/kg in single dose study and 20 mg/kg in the study dosed for 7 consecutive days. Read More

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January 2020

A Cohesin Subunit Variant Identified from a Peripheral Sclerocornea Pedigree.

Dis Markers 2019 12;2019:8781524. Epub 2019 Nov 12.

Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong.

Background: Sclerocornea is a rare congenital disorder characterized with the opacification of the cornea. Here, we report a nonconsanguineous Chinese family with multiple peripheral sclerocornea patients spanning across three generations inherited in an autosomal dominant manner.

Methods: This is a retrospective case series of a peripheral sclerocornea pedigree. Read More

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Cohesin cleavage by separase is enhanced by a substrate motif distinct from the cleavage site.

Nat Commun 2019 11 15;10(1):5189. Epub 2019 Nov 15.

Department of Physiology, University of California, San Francisco, CA, 94143, USA.

Chromosome segregation begins when the cysteine protease, separase, cleaves the Scc1 subunit of cohesin at the metaphase-to-anaphase transition. Separase is inhibited prior to metaphase by the tightly bound securin protein, which contains a pseudosubstrate motif that blocks the separase active site. To investigate separase substrate specificity and regulation, here we develop a system for producing recombinant, securin-free human separase. Read More

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November 2019

The cyclin B2/CDK1 complex inhibits separase activity in mouse oocyte meiosis I.

Development 2019 12 2;146(23). Epub 2019 Dec 2.

State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 100101 Beijing, China

Chromosome segregation is driven by separase, activity of which is inhibited by binding to securin and cyclin B1/CDK1. In meiosis, premature separase activity will induce aneuploidy or abolish chromosome segregation owing to the untimely destruction of cohesin. Recently, we have proved that cyclin B2 can compensate for cyclin B1 in CDK1 activation for the oocyte meiosis G2/M transition. Read More

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December 2019

Tumor-infiltrating lymphocytes and CD8 T cells predict survival of triple-negative breast cancer.

J Cancer Res Clin Oncol 2019 Dec 27;145(12):3105-3114. Epub 2019 Sep 27.

Department of Pathology, Institute of Biomedicine, University of Turku, Turku, Finland.

Purpose: Tumor inflammatory response was evaluated as a prognostic feature in triple-negative breast cancer (TNBC) and compared with the clinical prognosticators of breast cancer and selected biomarkers of cancer cell proliferation.

Methods: TNBC patients (n = 179) with complete clinical data and up to 18-year follow-up were obtained from Auria biobank, Turku University Hospital, Turku, Finland. Tumor-infiltrating lymphocytes (TILs) and several subtypes of inflammatory cells detected with immunohistochemistry were evaluated in different tumor compartments in full tissue sections and tissue microarrays. Read More

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December 2019

Identification of Bioactive Small Molecule Inhibitors of Separase.

ACS Chem Biol 2019 10 30;14(10):2155-2159. Epub 2019 Sep 30.

Department of Biology and Konstanz Research School Chemical-Biology (KoRS-CB) , University of Konstanz , Universitätsstraße 10 , 78467 Konstanz , Germany.

Separase, a cysteine protease of the CD clan, triggers chromosome segregation during mitosis by cleaving the cohesin ring entrapping the two sister chromatids. Deregulated separase activity is associated with aneuploidy, a hallmark of most human cancers. In fact, separase is highly overexpressed in many solid cancers, making it an attractive chemotherapeutic target. Read More

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October 2019

Spo13 prevents premature cohesin cleavage during meiosis.

Wellcome Open Res 2019 2;4:29. Epub 2019 Sep 2.

Wellcome Centre for Cell Biology, School of Biological Sciences, University of Edinburgh, Edinburgh, EH9 3BF, UK.

Meiosis produces gametes through two successive nuclear divisions, meiosis I and meiosis II. In contrast to mitosis and meiosis II, where sister chromatids are segregated, during meiosis I, homologous chromosomes are segregated. This requires the monopolar attachment of sister kinetochores and the loss of cohesion from chromosome arms, but not centromeres, during meiosis I. Read More

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September 2019