• SGO2-MAD2 can functionally replace securin and sequesters most separase in securin-knockout cells. (nature.com)
  • Acute loss of securin and SGO2, but not of either protein individually, resulted in separase deregulation associated with premature cohesin cleavage and cytotoxicity. (nature.com)
  • Thus, our results identify an unexpected function of SGO2 in mitotically dividing cells and a mechanism of separase regulation that is independent of securin but still supervised by the SAC. (nature.com)
  • Cryo-EM structure of a metazoan separase-securin complex at near-atomic resolution. (nature.com)
  • Separase can alternatively be inhibited by association with Cdk1-cyclin B1 but the corresponding complex is scarce in early mitosis and cannot explain why vertebrate securin is dispensable. (uni-bayreuth.de)
  • Silencing of the spindle assembly checkpoint (SAC) in metaphase enables the ubiquitin ligase APC/C to mediate the proteasomal destruction of securin (and cyclin B1), thereby activating separase. (uni-bayreuth.de)
  • 1) Securin associates co-translationally with separase and prevents its aggregation. (uni-bayreuth.de)
  • This suggests that it might assist the proper folding of this giant protease and offers a first mechanistic explanation for the genetic evidence that securin is not only an inhibitor but also an activator of separase. (uni-bayreuth.de)
  • While free securin is phosphorylated in mitosis, separase-bound securin is kept in an unphosphorylated state by associated PP2A. (uni-bayreuth.de)
  • This effecuates supernumerous securin to be degraded first and largely gone by the time separase-associated securin is targeted for proteolysis. (uni-bayreuth.de)
  • 3) Once liberated, separase is subject to conformational change by the peptidyl-prolyl isomerase Pin1 and thereby rendered resistant against residual securin. (uni-bayreuth.de)
  • 4) Pin1 catalyzed trans-to-cis isomerization of separase is essential for Cdk1-cyclin B1-dependent inhibition and explains why the kinase and securin bind separase in a mutually exclusive manner. (uni-bayreuth.de)
  • It is enabled by SAC-activated Mad2 to bind and inhibit separase and can functionally replace securin. (uni-bayreuth.de)
  • Acute depletion of Sgo2 and securin (but not the individual knock-downs) result in separase deregulation and premature loss of cohesion. (uni-bayreuth.de)
  • Securin degradation then unleashes separase to promote sister-chromatid separation. (biomedcentral.com)
  • Dephosphorylation results in a second peak of Cdk1-cyclin B1-separase complex formation in late mitosis when most cyclin B1 has already been degraded. (uni-bayreuth.de)
  • Separase universally triggers eukaryotic anaphases by cleavage of sister chromatid cohesion mediating cohesin. (uni-bayreuth.de)
  • 10) Cleavage of Mcl1 and Bcl-xL by separase transforms these pro-survival factors into proapoptotic fragments and triggers death in mitosis via the intrinsic pathway of apoptosis. (uni-bayreuth.de)
  • It is known that the final trigger of centriole disengagement is cleavage by separase. (uni-bayreuth.de)
  • Here, separase is activated and locally cleaves cohesin, which might grant the repair machinery access to the damaged DNA. (uni-bayreuth.de)
  • APC/C-dependent ubiquitylation and action of the AAA-ATPase TRIP13 in conjunction with the MAD2-specific adaptor p31 comet liberate separase from SGO2-MAD2 in vitro. (nature.com)
  • Fig. 4: TRIP13-p31 comet -dependent disassembly liberates separase from SGO2-MAD2. (nature.com)
  • 8) The AAA-ATPase Trip13 actively disassembles the separase-Sgo2-Mad2 complex upon SAC silencing in metaphase. (uni-bayreuth.de)
  • A family of highly conserved serine-threonine kinases that are involved in the regulation of MITOSIS. (rush.edu)
  • The activator Cdc20 is then replaced by a second activator, Cdh1, and APC/C Cdh1 promotes complete degradation of M cyclin, followed by polo-like kinase 1, Aurora A, and other substrates, to complete mitosis and cytokinesis and drive progression into G1 [ 1 , 2 ]. (biomedcentral.com)
  • Higher animals have three distinct forms of such cell divisions: Meiosis I and meiosis II are specialized forms of cell division occurring during generation of gametes (eggs and sperm) for sexual reproduction, mitosis is the form of cell division used by all other cells of the body. (wikipedia.org)
  • Meiosis II-nondisjunction may also result in aneuploidy syndromes, but only to a much smaller extent than do segregation failures in meiosis I. Division of somatic cells through mitosis is preceded by replication of the genetic material in S phase. (wikipedia.org)
  • Sgo2, the second vertebrate shugoshin, has an essential cohesin protective function in meiosis but why it is also expressed in mitosis remains largely enigmatic. (uni-bayreuth.de)
  • Eukaryotic cell divisions can be classified as mitosis (equational division) and meiosis (reductional division). (mathisfunforum.com)
  • Meiosis-II is like mitosis where the chromatids are separated. (mathisfunforum.com)
  • Despite being structurally related to caspases, separase has not been previously linked to apoptosis. (uni-bayreuth.de)
  • It is the separase itself that prevents the threatening consequences of its premature activity: it induces the dividing cell to undergo suicide, a process known as apoptosis. (healthcare-in-europe.com)
  • This happens because the separase re-purposes two proteins that usually have the task of counteracting apoptosis. (healthcare-in-europe.com)
  • 11) Mcl1 and Bcl-xL are substrates for separase only when phosphorylated by Nek2a. (uni-bayreuth.de)
  • Here, we used experimental and computational approaches to dissect the quantitative mechanisms underlying the ordered degradation of the substrates of the ubiquitin ligase APC/C Cdc20 , a key regulator of chromosome segregation in mitosis. (biomedcentral.com)
  • 6) Upon destruction of this last cyclin B1 in early G1 phase, separase is released from the late Cdk1-cyclin B1-separase complex and triggers centriole disengagement, thereby licensing later centrosome duplication. (uni-bayreuth.de)
  • Here we show that human shugoshin 2 (SGO2), an essential protector of meiotic cohesin with unknown functions in the soma 6 , 7 , is turned into a separase inhibitor upon association with SAC-activated MAD2. (nature.com)
  • Fig. 3: SGO2 is a MAD2-dependent, competitive inhibitor of separase. (nature.com)
  • Protein phosphatase 2A (PP2A) also binds separase but the physiological role of this interaction remains enigmatic. (uni-bayreuth.de)
  • Moreover, separase-dependent processing transforms MCL1 and BCL-XL from anti-apoptotic factors into pro-apoptotic protein fragments. (healthcare-in-europe.com)
  • The pre-replication complex (pre-RC) assembly or the DNA replication licensing is the first step in DNA replication initiation, characterized by the sequential recruitment of ORCs, Cdc6, Cdt1 and MCMs to the DNA replication origins to form the pre-RC at the end of mitosis ( Bell and Dutta 2002 ). (intechopen.com)
  • Simultaneous activity of both enzymes only occurs when cells rush through mitosis due to pathological loss of the SAC. (uni-bayreuth.de)
  • It ensures that the separase spares healthy cells and actually only attacks the proteins MCL1 and BCL-XL in the case of an imminent pathological cell development. (healthcare-in-europe.com)
  • Right: If the spindle assembly checkpoint is defective, the activities of NEK2A and separase timely overlap (purple area). (healthcare-in-europe.com)
  • However, if the spindle assembly checkpoint is defective, the process of cell division is accelerated: And while NEK2A is still present in the cell, the separase becomes active. (healthcare-in-europe.com)
  • Hellmuth and Stemmann refer to this interaction of the two enzymes they have discovered as the 'Minimal Duration of Early Mitosis Checkpoint', or 'DMC' for short. (healthcare-in-europe.com)
  • In this case, the separase fulfils its functions at the right time, without being able to identify and attack the no longer phosphorylated MCL1 and BCL-XL. (healthcare-in-europe.com)
  • Therefore, a promising approach in the fight against cancer could now be to encourage separase-dependent transformation of MCL1 and BCL-XL into pro-apoptotic factors because this would be especially harmful to diseased cells. (healthcare-in-europe.com)
  • As the protector of chromatid cohesion and centriole engagement Sgo1 is a key regulator for faithful mitosis. (uni-bayreuth.de)
  • 9) Human separase facilitates the repair of DNA double strand breaks (DSBs) by homologous recombination. (uni-bayreuth.de)
  • nature structural & molecular biology Abstract In the early stages of mitosis, cohesin is released from chromosome arms but not from centromeres. (cbinsights.com)
  • Main During mitosis, the duplicated genome needs to be accurately distributed over the two daughter cells. (cbinsights.com)
  • If the separase is activated too early, there is a risk of cellular transformation into malignant cancer cells. (healthcare-in-europe.com)
  • ESP1 , ESP1-myc13 and pGAL-SWE1 ESP1-13myc cells were grown in YEP + raffinose, arrested in mitosis with nocodazole and switched to YEP + galactose media to induce expression of Swe1. (figshare.com)
  • Nondisjunction during mitosis leads to one daughter receiving both sister chromatids of the affected chromosome while the other gets none. (wikipedia.org)
  • Fig. 1: MAD2-dependent binding of human SGO2 to separase. (nature.com)
  • Competition for PRPF8 availability alters the transcription-coupled splicing of RNAs in which weak 5′ splice sites predominate, enabling diversification of human gene expression during biological processes like mitosis. (biomedcentral.com)