Human Chromosome Segregation Involves Multi-Layered Regulation of Separase by the Peptidyl-Prolyl-Isomerase Pin1

Hellmuth, Susanne; Rata, Scott; Brown, Andreas; Heidmann, Stefan; Novák, Béla; Stemmann, Olaf

doi:10.1016/j.molcel.2015.03.025

Cited by 52 publications

(52 citation statements)

References 38 publications

(62 reference statements)

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“…4C). Although K D Cyc was assumed to be constant in this model, it is possible that cyclin B1 gains higher affinity to separase in anaphase (10,23), in which case the maximum concentration of cyclin B1-separase complex reaches to even higher levels. The model also raises the possibility that, cyclin B1 might contribute to inhibition of the sepa-chromatids in anaphase.…”

Section: Modeling the Complex Formation Of Securin And Cyclin B1 Withmentioning

confidence: 99%

Quantitative analyses of the metaphase-to-anaphase transition reveal differential kinetic regulation for securin and cyclin B1

et al. 2018

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Separation of sister chromatids is a drastic and irreversible step in the cell cycle. The key biochemistry behind this event is the proteolysis mediated by the ubiquitin ligase called the anaphase promoting complex, or APC/C. Securin and cyclin B1 are the two established substrates for APC/ C whose degradation releases separase and inactivates cyclin B1-dependent kinase 1 (cdk1), respectively, at the metaphase-to-anaphase transition. In this study, we have combined biochemical quantifications with mathematical simulations to characterize the kinetic regulation of securin and cyclin B1, in the cytoplasmic and chromosomal compartments, and found that they are differentially distributed and degraded with different rates. Modeling their interaction with separase predicted that activation timing of separase well coincides with the decline of securin-separase concentration in the cytoplasm. Notably, it also coincides with the peak of cyclin B1-separase level on chromosomes, which appeared crucial to coordinate the timing for separase activation and cdk1 inhibition. We have also conducted phosphoproteomic analysis and identified Ki67 as a chromosomal cdk1 substrate whose dephosphorylation is facilitated by cyclin B1-separase interaction in anaphase.Mitosis is characterized by a synchronous separation of sister chromatids at anaphase onset. The anaphase events are induced by the action of the AnaphasePromoting Complex, or APC/C. APC/C has a ubiquitin ligase activity, which mediates proteolysis of its substrate proteins, securin and cyclin B1, at the mitotic period called the metaphase-to-anaphase (M/ A) transition (19). Proteolysis of securin induces activation of separase whose protease activity cleaves cohesin connecting sister chromatids. Proteolysis of cyclin B1 down regulates its associated cyclin-dependent kinase 1, or cdk1. In addition, separase that had been released from securin is known to bind to cyclin B1, and contributes also to inactivate cdk1 (9, 23). The relative significance of this separase-mediated inhibition of cdk1 remains to be investigated, however. Inactivation of cdk1 will give rise to dephosphorylation of cdk1 substrates at anaphase. We yet know little about what those cdk1 substrates are and what the effects of their dephosphorylation might be (22). The release of sister chromatid cohesion and subsequent separation of sister chromatids must occur coordinately to ensure fail-safe chromosome segregation (12). Degradation kinetics for securin and cyclin B1 determines the timepoints when their protein levels drop below the thresholds to commence anaphase events and is proposed to be under a robust system (13). Live cell imaging analyses for flu-

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Section: Modeling the Complex Formation Of Securin And Cyclin B1 Withmentioning

confidence: 99%

Quantitative analyses of the metaphase-to-anaphase transition reveal differential kinetic regulation for securin and cyclin B1

et al. 2018

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“…Once separase is phosphorylated at S 1126 and S 1153 , and securin is degraded, the WW domain of Pin1 docks onto the pS 1153 P motif of separase, which facilitates the PPIase domain to act catalytically on pS 1126 P to transform separase from trans-conformer to cis-conformer. This conformation change facilitates cyclin-dependent kinase 1 (Cdk1)/cyclin B binding (Hellmuth et al, 2015b).…”

Section: Molecular Characteristics Of Separasementioning

confidence: 99%

“…Recent studies indicate that phosphorylation of separase is required to make a configuration switch in order to bind to Cdk1/cyclin B (Hellmuth et al, 2015b). The isomerase Pin1, a 17 kDa PPIase of the parvulin subfamily, is responsible for this switch.…”

Section: Regulation Of Separase Activitymentioning

confidence: 99%

“…The WW domain recruits Pin1 to separase by binding to pS 1153 P and enables the PPIase domain to engage pS 1126 P. Both depletion of Pin1 or chemical inhibition of Pin1's PPIase activity by epigallocat echin-3-gallate (EGCG) can inhibit cyclin B1 binding to separase. As a result, activated separase causes premature loss of sister-chromatid cohesion (Hellmuth et al, 2015b).…”

Section: Regulation Of Separase Activitymentioning

confidence: 99%

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Biology and insights into the role of cohesin protease separase in human malignancies

Zhang

Pati

2017

Biological Reviews

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Separase, an enzyme that resolves sister chromatid cohesion during the metaphase-to-anaphase transition, plays a pivotal role in chromosomal segregation and cell division. Separase protein, encoded by the extra spindle pole bodies like 1 (ESPL1) gene, is overexpressed in numerous human cancers including breast, bone, brain, and prostate. Separase is oncogenic, and its overexpression is sufficient to induce mammary tumours in mice. Either acute or chronic overexpression of separase in mouse mammary glands leads to aneuploidy and tumorigenesis, and inhibition of separase enzymatic activity decreases the growth of human breast tumour xenografts in mice. This review focuses on the biology of and insights into the molecular mechanisms of separase as an oncogene, and its significance and implications for human cancers.

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“…This finding provides a possible explanation for why only chromatin-bound cohesin is cleaved by separase, allowing the bulk of cohesin released by Wapl in prophase to remain intact and to be recycled in the next cell cycle. Moreover, a recent study showed that the phosphorylation-dependent peptidyl-prolyl cis/trans isomerase Pin1 catalyzes a conformational change of separase, presumably involving a proline cis/trans isomerization event [107]. In early mitosis, Pin1 is required for cyclin B1-Cdk1-dependent inhibition of separase.…”

Section: Cohesin Release From Chromosomesmentioning

confidence: 99%

Regulation of sister chromatid cohesion during the mitotic cell cycle

2015

Sci. China Life Sci.

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Orderly execution of two critical events during the cell cycle--DNA replication and chromosome segregation--ensures the stable transmission of genetic materials. The cohesin complex physically connects sister chromatids during DNA replication in a process termed sister chromatid cohesion. Timely establishment and dissolution of sister chromatid cohesion is a prerequisite for accurate chromosome segregation, and is tight regulated by the cell cycle machinery and cohesin-associated proteins. In this review, we discuss recent progress in the molecular understanding of sister chromatid cohesion during the mitotic cell cycle.cell cycle, mitosis, sister chromatid cohesion, cohesin, cohesin loading, cohesin release, DNA replication, cohesion establishment Citation:Zheng G, Yu HT. Regulation of sister chromatid cohesion during the mitotic cell cycle. Sci China Life Sci, 2015Sci, , 58: 1089Sci, -1098Sci, , doi: 10.1007 During the cell cycle, DNA undergoes replication during S phase to generate two identical copies of each chromosome, called sister chromatids. During mitosis, sister chromatids are separated and partitioned evenly to the two daughter cells to maintain genomic stability. Cells receive too many or too few chromosomes become aneuploid. Aneuploidy can drive tumorigenesis in a context-dependent manner [1,2]. To prevent premature sister chromatid separation and ensure accurate chromosome segregation, sister chromatids are physically tethered to each other through the process of sister chromatid cohesion, as well as DNA catenation, from S phase till metaphase. Sister chromatid cohesion is mediated by the highly conserved ring-shaped cohesin complex, which topologically entraps chromosomes [3,4]. Cohesion establishment, maintenance, and removal at different cell cycle phases require a series of coordinated interactions between cohesin and its regulators (Figure 1). Cohesin is loaded onto DNA by the cohesin loader complex Scc2-Scc4 in telophase and early G1 [57]. At this stage, the chromatin-bound cohesin is highly dynamic, and can be released from chromosomes by the cohesin releasing factor Wapl, with the help of the scaffold protein Pds5 [811]. During S phase, the replicated sister chromatids are tethered by cohesin to establish sister chromatid cohesion. Cohesion establishment requires the acetylation of two adjacent, evolutionarily conserved lysines on Smc3 by the acetyltransferase Eco1 (Esco1/2 in vertebrates) [1217], and in metazoans, the subsequent recruitment of sororin to cohesin through Pds5 [1821]. Smc3 acetylation and sororin antagonize the cohesin-releasing activity of Wapl-Pds5, thereby stabilizing cohesin on chromosomes [17,21]. Finally, in mitosis, cohesin is released from chromosomes in a stepwise manner in vertebrates [22]. In early mitosis, Pds5-bound sororin is phosphorylated by mitotic kinases and dissociates from cohesin [21,2325]. Sororin dissociation allows Wapl to gain access to Pds5 and cohesin, releasing cohesin from chromosome arms. At centromeres,

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Human Chromosome Segregation Involves Multi-Layered Regulation of Separase by the Peptidyl-Prolyl-Isomerase Pin1

Cited by 52 publications

References 38 publications

<b>Quantitative analyses of the metaphase-to-anaphase transition reveal differential kinetic regulation for securin and cyclin </b><b>B1 </b>

<b>Quantitative analyses of the metaphase-to-anaphase transition reveal differential kinetic regulation for securin and cyclin </b><b>B1 </b>

Biology and insights into the role of cohesin protease separase in human malignancies

Regulation of sister chromatid cohesion during the mitotic cell cycle

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