Nek2A destruction marks APC/C activation at the prophase-to-prometaphase transition by spindle-checkpoint restricted Cdc20

Boekhout, Michiel; Wolthuis, Rob M. F.

doi:10.1242/jcs.163279

Cited by 19 publications

(27 citation statements)

References 73 publications

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“…These results indicate that the main contributor for efficient ubiquitination of Nek2A by APC/C Cdc20 is the MR tail. This agrees with previous studies showing that in cells, D‐box and KEN‐box mutants only mildly affect Nek2A degradation kinetics, in contrast to the strong effects of disrupting the MR tail . Despite the non‐essential roles of the D‐ and KEN‐boxes, Nek2A ubiquitination by the recombinant APC/C is Cdc20‐dependent, confirming previous studies (Fig C) .…”

Section: Resultssupporting

confidence: 92%

A unique binding mode of Nek2A to the APC /C allows its ubiquitination during prometaphase

2020

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The anaphase‐promoting complex (APC/C) is the key E3 ubiquitin ligase which directs mitotic progression and exit by catalysing the sequential ubiquitination of specific substrates. The activity of the APC/C in mitosis is restrained by the spindle assembly checkpoint (SAC), which coordinates chromosome segregation with the assembly of the mitotic spindle. The SAC effector is the mitotic checkpoint complex (MCC), which binds and inhibits the APC/C. It is incompletely understood how the APC/C switches substrate specificity in a cell cycle‐specific manner. For instance, it is unclear how in prometaphase, when APC/C activity towards cyclin B and securin is repressed by the MCC, the kinase Nek2A is ubiquitinated. Here, we combine biochemical and structural analysis with functional studies in cells to show that Nek2A is a conformational‐specific binder of the APC/C–MCC complex (APC/CMCC) and that, in contrast to cyclin A, Nek2A can be ubiquitinated efficiently by the APC/C in conjunction with both the E2 enzymes UbcH10 and UbcH5. We propose that these special features of Nek2A allow its prometaphase‐specific ubiquitination.

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Section: Resultssupporting

confidence: 92%

A unique binding mode of Nek2A to the APC /C allows its ubiquitination during prometaphase

2020

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“…The N terminus of cyclin A is able to bind Cdc20 with an affinity that may allow it to outcompete spindle checkpoint proteins (Di Fiore and Pines, 2010). However, the rate of cyclin A2 destruction may still be reduced by highly active checkpoint signaling (Boekhout and Wolthuis, 2015), presumably due to much greater competition for Cdc20 from checkpoint proteins. This suggests that the destruction of cyclin A2 remains at least partially coupled to the activity of the checkpoint in early prometaphase.…”

Section: Discussionmentioning

confidence: 99%

“…This provides the oocyte with two pools of cyclin B1, which are then destroyed over different time periods: an excess of free cyclin B1, which is preferentially destroyed in late prometaphase, and a pool of CDK1-bound cyclin B1, which is preserved until metaphase. Known prometaphase APC/C substrates such as cyclin A2, which must be destroyed to allow passage into metaphase, contain motifs in addition to the D-box, which make their destruction less reliant on high levels of checkpoint-free Cdc20, thereby permitting them to escape full checkpoint inhibition (Di Fiore and Pines, 2010, Wolthuis et al., 2008, van Zon and Wolthuis, 2010, Boekhout and Wolthuis, 2015). Here, we uncover such a motif in cyclin B1.…”

Section: Introductionmentioning

confidence: 99%

Aneuploidy in Oocytes Is Prevented by Sustained CDK1 Activity through Degron Masking in Cyclin B1

et al. 2019

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SummarySuccessful mitosis requires that cyclin B1:CDK1 kinase activity remains high until chromosomes are correctly aligned on the mitotic spindle. It has therefore been unclear why, in mammalian oocyte meiosis, cyclin B1 destruction begins before chromosome alignment is complete. Here, we resolve this paradox and show that mouse oocytes exploit an imbalance in the ratio of cyclin B1 to CDK1 to control CDK1 activity; early cyclin B1 destruction reflects the loss of an excess of non-CDK1-bound cyclin B1 in late prometaphase, while CDK1-bound cyclin B1 is destroyed only during metaphase. The ordered destruction of the two forms of cyclin B1 is brought about by a previously unidentified motif that is accessible in free cyclin B1 but masked when cyclin B1 is in complex with CDK1. This protects the CDK1-bound fraction from destruction in prometaphase, ensuring a period of prolonged CDK1 activity sufficient to achieve optimal chromosome alignment and prevent aneuploidy.

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“…The turquoise module has hub genes involved in ion transmembrane transport, including VPS9D1 , KCNN1 , PRKAB2 and NDUFA4 (Table ; Boettger et al., ; Pitceathly et al., ; Sugimoto, Hatakeyama, & Isobe, ; Steinberg & Kemp, ); this observation together with the upregulation of the Magenta module, which is enriched for ion transport processes (Table ), suggests that ion transportation is activated in depigmented opossums. In contrast, several of the hub genes in the blue module participate in cell cycle processes, including TOP2B , NEK2 , KNSTRN , CDK5RAP2 , UBE2C and PBK (Table ), these genes act as positive signals for cell division (i.e., NEK2 , KNSTRN , CDK5RAP2 , UBE2C and PBK ; Boekhout & Wolthuis, ; Fang, Seki, & Fang, ; Rape & Kirschner, ; Rizkallah, Batsomboon, Dudley, & Hurt, ; Zhang et al., ) or for DNA replication (i.e., TOP2B ; Sakaguchi & Kikuchi, ). The downregulation of these genes in depigmented individuals and of other genes in the blue module (Tables , ) may indicate the inhibition of cellular proliferation in depigmented skin.…”

Section: Resultsmentioning

confidence: 99%

Transcriptomic analysis of skin pigmentation variation in the Virginia opossum (Didelphis virginiana)

Nigenda‐Morales

Beasley

et al. 2018

Molecular Ecology

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Skin pigmentation and coat pigmentation are two of the best-studied examples of traits under natural selection given their quantifiable fitness interactions with the environment (e.g., camouflage) and signalling with other organisms (e.g., warning coloration). Previous morphological studies have found that skin pigmentation variation in the Virginia opossum (Didelphis virginiana) is associated with variation in precipitation and temperatures across its distribution range following Gloger's rule (lighter pigmentation in temperate environments). To investigate the molecular mechanism associated with skin pigmentation variation, we used RNA-Seq and quantified gene expression of wild opossums from tropical and temperate populations. Using differential expression analysis and a co-expression network approach, we found that expression variation in genes with melanocytic and immune functions is significantly associated with the degree of skin pigmentation variation and may be underlying this phenotypic difference. We also found evidence suggesting that the Wnt/β-catenin signalling pathway might be regulating the depigmentation observed in temperate populations. Based on our study results, we present several alternative hypotheses that may explain Gloger's rule pattern of skin pigmentation variation in opossum, including changes in pathogen diversity supporting a pathogen-resistant hypothesis, thermal stress associated with temperate environments, and pleiotropic and epistatic interactions between melanocytic and immune genes.

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Nek2A destruction marks APC/C activation at the prophase-to-prometaphase transition by spindle-checkpoint restricted Cdc20

Abstract: Nek2 isoform A (Nek2A) is a presumed substrate of the anaphasepromoting complex/cyclosome containing Cdc20 (APC/C Cdc20

Cited by 19 publications

References 73 publications

A unique binding mode of Nek2A to the APC /C allows its ubiquitination during prometaphase

A unique binding mode of Nek2A to the APC /C allows its ubiquitination during prometaphase

Aneuploidy in Oocytes Is Prevented by Sustained CDK1 Activity through Degron Masking in Cyclin B1

Transcriptomic analysis of skin pigmentation variation in the Virginia opossum (Didelphis virginiana)

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