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extra spindle pole bodies like 1, separase OKDB#: 2758
 Symbols: ESPL1 Species: human
 Synonyms: ESP1, SEPA  Locus: 12q13.13 in Homo sapiens

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General Comment Segregating Chromosomes in the Mammalian Oocyte. Mihajlović AI et al. (2019) Chromosome segregation errors in human oocytes lead to aneuploid embryos that cause infertility and birth defects. Here we provide an overview of the chromosome-segregation process in the mammalian oocyte, highlighting mechanistic differences between oocytes and somatic cells that render oocytes so prone to segregation error. These differences include the extremely large size of the oocyte cytoplasm, the unique geometry of meiosis-I chromosomes, idiosyncratic function of the spindle assembly checkpoint, and dramatically altered oocyte cell-cycle control and spindle assembly, as compared to typical somatic cells. We summarise recent work suggesting that aging leads to a further deterioration in fidelity of chromosome segregation by impacting multiple components of the chromosome-segregation machinery. In addition, we compare and contrast recent results from mouse and human oocytes, which exhibit overlapping defects to differing extents. We conclude that the striking propensity of the oocyte to mis-segregate chromosomes reflects the unique challenges faced by the spindle in a highly unusual cellular environment.////////////////// Meiosis: separase strikes twice. Terret ME et al. During anaphase, the cysteine protease separase cleaves cohesin and releases sister chromatids. In budding yeast, separase also has a crucial non-proteolytic role in triggering mitotic exit. Separase performs a similar non-catalytic function in frog and mouse oocytes through its physical interaction with cdk1. Vertebrate separase is therefore essential not only for homologue disjunction, but also for bringing about the end of meiosis I.

NCBI Summary: Stable cohesion between sister chromatids before anaphase and their timely separation during anaphase are critical for chromosome inheritance. In vertebrates, sister chromatid cohesion is released in 2 steps via distinct mechanisms. The first step involves phosphorylation of STAG1 (MIM 604358) or STAG2 (MIM 300826) in the cohesin complex. The second step involves cleavage of the cohesin subunit SCC1 (RAD21; MIM 606462) by ESPL1, or separase, which initiates the final separation of sister chromatids (Sun et al., 2009 [PubMed 19345191]).[supplied by OMIM, Nov 2010]
General function Chromosome organization
Comment Detection of Separase Activity Using a Cleavage Sensor in Live Mouse Oocytes. Nikalayevich E et al. (2018) Separase proteolytically removes cohesin complexes from sister chromatid arms in meiosis I, which is essential for chromosome segregation. Regulation of separase activity is essential for proper cell cycle progression and correct chromosome segregation. Onset of endogenous separase activity has not yet been observed in live oocytes.We describe here a method for detecting separase activity in mouse oocytes in vivo. This method utilizes a previously described cleavage sensor made up of H2B-mCherry fused with Scc1(107-268 aa)-YFP. The cleavage sensor is loaded on the chromosomes through its H2B-tag, and the signal from both mCherry and YFP is visible. Upon separase activation the Scc1 fragment is cleaved and YFP dissociates from the chromosomes. The change in the ratio between mCherry and YFP fluorescence intensity is a readout of separase activity.//////////////////
Cellular localization Nuclear
Ovarian function Oogenesis, Oocyte maturation
Comment Essential CDK1-inhibitory role for separase during meiosis I in vertebrate oocytes. Gorr IH et al. Separase not only triggers anaphase of meiosis I by proteolytic cleavage of cohesin on chromosome arms, but in vitro vertebrate separase also acts as a direct inhibitor of cyclin-dependent kinase 1 (Cdk1) on liberation from the inhibitory protein, securin. Blocking separase-Cdk1 complex formation by microinjection of anti-separase antibodies prevents polar-body extrusion in vertebrate oocytes. Importantly, proper meiotic maturation is rescued by chemical inhibition of Cdk1 or expression of Cdk1-binding separase fragments lacking cohesin-cleaving activity.
Expression regulated by
Ovarian localization Oocyte
Comment The meiosis I-to-meiosis II transition in mouse oocytes requires separase activity Terret ME, et al . Faithful segregation of homologous chromosomes during the first meiotic division is essential for further embryo development. The question at issue is whether the same mechanisms ensuring correct separation of sister chromatids in mitosis are at work during the first meiotic division. In mitosis, sister chromatids are linked by a cohesin complex holding them together until their disjunction at anaphase. Their disjunction is mediated by Separase, which cleaves the cohesin. The activation of Separase requires prior degradation of its associated inhibitor, called securin. Securin is a target of the APC/C (Anaphase Promoting Complex/Cyclosome), a cell cycle-regulated ubiquitin ligase that ubiquitinates securin at the metaphase-to-anaphase transition and thereby targets it for degradation by the 26S proteasome. After securin degradation, Separase cleaves the cohesins and triggers chromatid separation, a prerequisite for anaphase. In yeast and worms, the segregation of homologous chromosomes in meiosis I depends on the APC/C and Separase activity. Yet, it is unclear if Separase is required for the first meiotic division in vertebrates because APC/C activity is thought to be dispensable in frog oocytes. We therefore investigated if Separase activity is required for correct chromosome segregation in meiosis I in mouse oocytes.
Follicle stages
Mutations 1 mutations

Species: mouse
Mutation name: None
type: null mutation
fertility: infertile - ovarian defect
Comment: Resolution of chiasmata in oocytes requires separase-mediated proteolysis. Kudo NR et al. In yeast, resolution of chiasmata in meiosis I requires proteolytic cleavage along chromosome arms of cohesin's Rec8 subunit by separase. Since activation of separase by the anaphase-promoting complex (APC/C) is supposedly not required for meiosis I in Xenopus oocytes, it has been suggested that animal cells might resolve chiasmata by a separase-independent mechanism related to the so-called 'prophase pathway' that removes cohesin from chromosome arms during mitosis. By expressing Cre recombinase from a zona pellucida promoter, we have deleted a floxed allele of separase specifically in mouse oocytes. This prevents removal of Rec8 from chromosome arms and resolution of chiasmata. It also hinders extrusion of the first polar body (PBE) and causes female sterility. mRNA encoding wild-type but not catalytically inactive separase restores chiasma resolution. Both types of mRNA restore PBE. Proteolytic activity of separase is therefore essential for Rec8's removal from chromosome arms and for chiasma resolution but not for PBE.

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created: March 12, 2005, 8:49 a.m. by: hsueh   email:
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last update: Feb. 14, 2020, 3:07 p.m. by: hsueh    email:

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