A prometaphase mechanism of securin destruction is essential for meiotic progression in mouse oocytes

Thomas, Christopher; Wetherall, Benjamin; Levasseur, Mark; Harris, Rebecca J.; Kerridge, Scott; Higgins, Jonathan M.G.; Davies, Owen R.; Madgwick, Suzanne

doi:10.1038/s41467-021-24554-2

Cited by 12 publications

(9 citation statements)

References 83 publications

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“…This nuclear pool of IFY-1 is therefore likely not bound to separase. An excess pool of securin is also found in mammalian oocytes and serves as a competitive substrate of APC/C to time cell cycle events (Thomas et al, 2021). At NEBD through prometaphase I, IFY-1 localizes similarly to SEP-1 at kinetochore cups on the chromosomes, and linear elements in the cortex (Fig.…”

Section: Resultsmentioning

confidence: 99%

Securin Regulates the Spatiotemporal Dynamics of Separase

Turpin,

Sloan,

LaForest

et al. 2023

Preprint

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Separase is a key regulator of the metaphase to anaphase transition with multiple functions. Separase cleaves cohesin to allow chromosome segregation and localizes to vesicles to promote exocytosis in mid-anaphase. The anaphase promoting complex/cyclosome (APC/C) activates separase by ubiquitinating its inhibitory chaperone, securin, triggering its degradation. How this pathway controls the exocytic function of separase has not been investigated. During meiosis I, securin is degraded over several minutes, while separase rapidly relocalizes from kinetochore structures at the spindle and cortex to sites of action on chromosomes and vesicles at anaphase onset. The loss of cohesin coincides with the relocalization of separase to the chromosome midbivalent at anaphase onset. APC/C depletion prevents separase relocalization, while securin depletion causes precocious separase relocalization. Expression of non-degradable securin inhibits chromosome segregation, exocytosis, and separase localization to vesicles but not to the anaphase spindle. We conclude that APC/C mediated securin degradation controls separase localization. This spatiotemporal regulation will impact the effective local concentration of separase for more precise targeting of substrates in anaphase.

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Section: Resultsmentioning

confidence: 99%

Securin Regulates the Spatiotemporal Dynamics of Separase

Turpin,

Sloan,

LaForest

et al. 2023

Preprint

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“…One plausible target of Cdk1/Cyclin B1 could be Separase, which we identify as a key regulatory of premature centriole disengagement, and which is inhibited by Cdk1/CyclinB1 activity 49 . The synchronous loss of Securin and Cyclin-B1 at anaphase onset by APC/C Cdc20 could thus not only activate Separase to induce chromosome segregation 50 , but also permit centriole disengagement under the control of Plk1. A second important question is how Separase can act on centrosomes in G2 in Aphidicolin-treated cells without affecting chromosome cohesion.…”

Section: Discussionmentioning

confidence: 99%

Mild replication stress causes premature centriole disengagement via a sub-critical Plk1 activity under the control of ATR-Chk1

Dwivedi

Harry

Meraldi

2022

Preprint

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A tight synchrony between the DNA and centrosome cycle is essential for genomic integrity. Centriole disengagement, which licenses centrosomes for duplication, occurs normally during mitotic exit. We recently demonstrated that mild DNA replication stress in untransformed human cells causes premature centriole disengagement at mitotic entry, leading to transient multipolar spindles that favour chromosome mis-segregation. How mild replication stress accelerate the centrosome cycle at the molecular level remained, however, unclear. Using expansion microscopy, we show that mild replication stress already induces premature centriole disengagement in G2 via the ATR-Chk1 axis of the DNA damage repair pathway. We demonstrate that this results in a subcritical Plk1 kinase activity that is insufficient for rapid mitotic entry. Nevertheless, it primes the pericentriolar matrix for Separase-dependent disassembly causing premature centriole disengagement in G2. We postulate that the differential requirement of Plk1 activity in the DNA and centrosome cycles explains how mild replication stress disrupts the synchrony between both processes and contributes to genomic instability.

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“…Additionally, PP1-mediated dephosphorylation of CDC20 plays a role in activating APC/C CDC20 , the major E3 ligase involved in the degradation of pro-M-Phase proteins at metaphase/anaphase transition (Bancroft et al, 2020; Kim et al, 2017). Degradation of the APC/C CDC20 substrates securin and cyclin B starts in prometaphase of oocytes and is essential for metaphase I/anaphase I transition and accurate chromosome segregation (Levasseur et al, 2019; Thomas et al, 2021). Consequently, PP1 inhibition in oocytes at prometaphase may alter the degradation kinetics of proteins, impacting M-Phase progression.…”

Section: Discussionmentioning

confidence: 99%

M-Phase oscillations in PP1 activity are essential for accurate progression through mammalian oocyte meiosis

Camlin

Venkatachalam

Evans

2021

Preprint

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Tightly controlled fluctuations in kinase and phosphatase activity play important roles in regulating M-Phase transitions (e.g., G2/M). Protein Phosphatase 1 (PP1) is one of these phosphatases, with oscillations in activity driving mitotic M-Phase entry, progression, and exit, with evidence from a variety of experimental systems pointing to roles in meiosis as well. Here we report that PP1 is important for M-Phase transitions through mouse oocyte meiosis. Employing a unique small-molecule approach to inhibit or activate PP1 at distinct phases of mouse oocyte meiosis, we found that aberrations in normal cyclical PP1 activity leads to meiotic abnormalities. We report here that temporal control of PP1 activity is essential for G2/M transition, metaphase I/anaphase I transition, and the formation of a normal metaphase II oocyte. Our data also reveal that inappropriate activation of PP1 is more deleterious at G2/M transition than at prometaphase I-to-metaphase I, and that an active pool of PP1 during prometaphase I is vital for metaphase I/anaphase I transition and metaphase II chromosome alignment. Taken together, these results establish that loss of oscillations in PP1 activity causes a range of severe meiotic defects, pointing to essential roles for PP1 in oocytes and female fertility, and more broadly, M-Phase regulation.

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A prometaphase mechanism of securin destruction is essential for meiotic progression in mouse oocytes

Cited by 12 publications

References 83 publications

Securin Regulates the Spatiotemporal Dynamics of Separase

Securin Regulates the Spatiotemporal Dynamics of Separase

Mild replication stress causes premature centriole disengagement via a sub-critical Plk1 activity under the control of ATR-Chk1

M-Phase oscillations in PP1 activity are essential for accurate progression through mammalian oocyte meiosis

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