Cyclin B3 promotes anaphase I onset in oocyte meiosis

Karasu, Mehmet E.; Bouftas, Nora; Keeney, Scott; Wassmann, Katja

doi:10.1083/jcb.201808091

Cited by 51 publications

(83 citation statements)

References 76 publications

(121 reference statements)

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“…To assess whether degradation of securin and cyclin B1 in prometaphase caused separase activation, we used a separase activity biosensor generated by Nam et al that has previously been validated in oocytes 37–39 . The sensor consists of nucleosome-targeted H2B protein fused to eGFP and mCherry fluorophores.…”

Section: Resultsmentioning

confidence: 99%

“…However we suggest that, similar to other prometaphase APC/C substrates, this region of securin could be involved in either direct binding to the APC/C or in outcompeting spindle assembly checkpoint protein inhibition of APC/C-Cdc20 47–50 . In addition, cyclin B3 has recently been shown to have an important role in mouse oocyte MI in priming the APC/C for securin and cyclin B1 destruction 39,51,52 . Therefore an alternative possibility is that this region in securin is regulated by cyclin B3 and involved in an oocyte-specific APC/C activation mechanism.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Synchronous chromosome segregation in mouse oocytes is ensured by biphasic securin destruction and cyclin B1-Cdk1

Thomas

Levasseur

Harris

et al. 2019

Preprint

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Successful cell division relies on the faithful segregation of chromosomes. 13 If chromosomes segregate prematurely the cell is at risk of aneuploidy. Alternatively, 14 if cell division is attempted in the absence of complete chromosome segregation, non-15 segregated chromosomes can become trapped within the cleavage furrow and the cell 16 can lose viability. Securin plays a key role in this process, acting as a pseudosubstrate 17 to inhibit the protease separase that functions to cleave the cohesin rings that hold 18 chromosomes together. Consequently, securin must be depleted ahead of anaphase, 19 ensuring chromosome segregation occurs in time with the anaphase trigger. Here we 20 find that MI mouse oocytes contain a large excess of securin over separase and reveal 21 the existence of a novel mechanism that functions to promote the destruction of 22 excess securin in prometaphase. Critically, this mechanism relies on key residues that 23 are only exposed when securin is not bound to separase. We suggest that the majority 24 of non-separase bound securin is removed by this mechanism, allowing for separase 25 activity to be protected until just before anaphase. In addition, we further demonstrate 26 the importance of complementary mechanisms of separase inhibition by directly 27 measuring cleavage activity in live oocytes, confirming that both securin and 28 inhibition by cyclin B1-Cdk1 are independently sufficient to prevent premature 29 separase activation. 30 31 32 33 34 timed correctly. In situations where these events become disconnected, anaphase is 66 defective 23-25 . 67 In mitosis, the synchronous loss of cyclin B1 and securin is ensured by the similarity 68 of their destruction mechanisms. Both are ubiquitylated by the Anaphase Promoting 69 Complex/Cyclosome (APC/C) in metaphase 26,27 . Critically, this ubiquitylation relies 70 on both the availability of the APC/C activator protein Cdc20 and on a short linear 71 motif known as the D-box present in the N-terminus of both securin and cyclin B1 28-72 30 . Once all chromosomes are properly attached to spindle microtubules in metaphase, 73 Cdc20 and the APC/C form a bipartite receptor for D-box docking, triggering securin 74 and cyclin B1 destruction by the proteasome 31,32 . Prior to this, Cdc20 is sequestered 75 by the spindle assembly checkpoint (SAC), a diffusible signal generated at each 76 unattached kinetochore. The SAC functions to prevent docking of D-box motifs to the 77 APC/C and thereby inhibit anaphase until all chromosomes are attached to spindle 78 microtubules 33,34 . 79In contrast, securin and cyclin B1 destruction in mouse oocyte meiosis I is initiated in 80 prometaphase, prior to full chromosome alignment 35,36 . Initially this might seem like a 81 failure to ensure accurate chromosome segregation. However, our recent work 82 demonstrates that degradation of cyclin B1 in prometaphase is in fact a key feature of 83 a mechanism that functions to prevent aneuploidy in mouse oocytes 36 . At this time 84 point, destruction represents...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Synchronous chromosome segregation in mouse oocytes is ensured by biphasic securin destruction and cyclin B1-Cdk1

Thomas

Levasseur

Harris

et al. 2019

Preprint

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show abstract

“…Despite prominent, regulated expression during spermatogenesis, Ccnb3-deficient males are fully fertile and exhibit no gross meiotic abnormalities. While we cannot exclude the possibility that the em1 allele retains partial Ccnb3 function, our molecular characterization of mRNA and protein expression in testes (this study) and the strong metaphase I arrest in homozygous mutant oocytes (Karasu et al 2019) show that this allele is at least a substantial loss-of-function mutation. Furthermore, an independently generated Ccnb3 mutation that similarly causes oocyte arrest was also reported to support normal male fertility .…”

Section: Discussionmentioning

confidence: 67%

Cyclin B3 is dispensable for mouse spermatogenesis

Karasu

Keeney

2019

Preprint

Self Cite

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Cyclins, as regulatory partners of cyclin-dependent kinases (CDKs), control the switch-like cell cycle transitions that orchestrate orderly duplication and segregation of genomes. Compared to mitosis, relatively little is known about how cyclin-CDK complexes control meiosis, the specialized cell division that generates gametes for sexual production. Mouse cyclin B3 was previously shown to have expression restricted to the beginning of meiosis, making it a candidate to regulate meiotic events. Indeed, female mice lacking cyclin B3 are sterile because oocytes arrest at the metaphase-toanaphase transition of meiosis I. However, whether cyclin B3 functions during spermatogenesis was untested. Here, we found that males lacking cyclin B3 are fertile and show no detectable defects in spermatogenesis based on histological analysis of seminiferous tubules. Cytological analysis further showed no detectable defects in homologous chromosome synapsis or meiotic progression, and suggested that recombination is initiated and completed efficiently. Moreover, absence of cyclin B3 did not exacerbate previously described meiotic defects in mutants deficient for cyclin E2, suggesting a lack of redundancy between these cyclins. Thus, unlike in females, cyclin B3 is not essential for meiosis in males despite its prominent meiosis-specific expression.

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“…Similarly, in mouse oocytes, silencing Mad2 does not rescue the meiotic metaphase arrest upon Cyclin B3 depletion (Zhang et al, 2015a). In other studies, SAC markers on kinetochores did not persist in metaphase-arrested Ccnb3 KO oocytes, and SAC inactivation by chemical inhibition of Mps1 did not restore anaphase (Karasu et al, 2019;Li et al, 2019b).…”

Section: Introductionmentioning

confidence: 76%

“…Based on results obtained in flies and mice, it has been suggested that CycB3 may function upstream of the APC/C to activate it (Karasu et al, 2019;Li et al, 2019b;Yuan and O'Farrell, 2015;Zhang et al, 2015a). We decided to test this hypothesis.…”

Section: Cycb3 Functions Upstream Of the Apc/c And Collaborates With mentioning

confidence: 99%

Cyclin B3 activates the Anaphase-Promoting Complex/Cyclosome in meiosis and mitosis

Garrido

Bourouh

Bonneil

et al. 2020

Preprint

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In mitosis and meiosis, chromosome segregation is triggered by the Anaphase-Promoting Complex/Cyclosome (APC/C), a multi-subunit ubiquitin ligase that targets proteins for degradation, leading to the separation of chromatids. APC/C activation requires phosphorylation of its APC3 and APC1 subunits, which allows the APC/C to bind its Cdc20 co-activator. The identity of the kinase(s) responsible for APC/C activation in vivo is unclear. Cyclin B3 is required for meiotic anaphase in flies, worms and vertebrates, but whether it activates the APC/C is unclear. We found that Drosophila Cyclin B3 (CycB3) collaborates with PP2A-B55/Tws in embryonic development, indicating that CycB3 also promotes anaphase in mitosis. Moreover, CycB3 promotes APC/C activity and anaphase in cells in culture. We show that CycB3 physically associates with the APC/C, is required for phosphorylation of APC3, and promotes APC/C association with its co-activators. We propose that CycB3-Cdk1 directly phosphorylates the APC/C to activate it in both meiosis and mitosis.

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Cyclin B3 promotes anaphase I onset in oocyte meiosis

Cited by 51 publications

References 76 publications

Synchronous chromosome segregation in mouse oocytes is ensured by biphasic securin destruction and cyclin B1-Cdk1

Synchronous chromosome segregation in mouse oocytes is ensured by biphasic securin destruction and cyclin B1-Cdk1

Cyclin B3 is dispensable for mouse spermatogenesis

Cyclin B3 activates the Anaphase-Promoting Complex/Cyclosome in meiosis and mitosis

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