Building a Regulatory Network with Short Linear Sequence Motifs: Lessons from the Degrons of the Anaphase-Promoting Complex

Davey, Norman E.; Morgan, David

doi:10.1016/j.molcel.2016.09.006

Cited by 147 publications

(173 citation statements)

References 98 publications

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“…No reaccumulation of cyclin B3-RFP was observed as oocytes progressed into meiosis II. Deleting the D-box stabilized cyclin B3-RFP ( Figure 5C) (the protein has no obvious KEN-box or ABBA motif [45]. These findings support the conclusion that cyclin B3 is an APC/C substrate in oocyte meiosis.…”

supporting

confidence: 79%

Cyclin B3 promotes APC/C activation and anaphase I onset in oocyte meiosis

Bouftas

Keeney

et al. 2018

Preprint

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As obligate kinase partners, cyclins control the switch-like cell cycle transitions that orchestrate orderly duplication and segregation of genomes. Meiosis, the cell division that generates gametes for sexual reproduction, poses unique challenges because two rounds of chromosome segregation must be executed without intervening DNA replication. Mammalian cells express numerous, temporally regulated cyclins, but how these proteins collaborate to control meiosis remains poorly understood. Here, we delineate an essential function for mouse cyclin B3 in the first meiotic division of oocytes. Females genetically ablated for cyclin B3 are viable, indicating the protein is dispensable for mitotic divisions, but are sterile. Mutant oocytes appear normal until metaphase I but then display a highly penetrant failure to transition to anaphase I. They arrest with hallmarks of defective APC/C activation, including no separase activity and high MPF, cyclin B1, and securin levels. Partial APC/C activation occurs, however, as exogenously expressed APC/C substrates can be degraded and arrest can be suppressed by inhibiting MPF kinase. Cyclin B3 is itself targeted for degradation by the APC/C. Cyclin B3 forms active kinase complexes with CDK1, and meiotic progression requires cyclin B3-associated kinase activity. Collectively, our findings indicate that cyclin B3 is essential for oocyte meiosis because it fine-tunes APC/C activity as a kinase-activating CDK partner. Cyclin B3 homologs from frog, zebrafish, and fruitfly rescue meiotic progression in cyclin B3-deficient mouse oocytes, indicating conservation of the biochemical properties and possibly cellular functions of this germline-critical cyclin. IntroductionEukaryotic cell division depends on oscillations of cyclindependent kinases (CDKs) associated with specific cyclins [1][2][3][4]. In vertebrate somatic cells, progression from G1 into S phase, G2, and mitosis depends on the cyclin D family, followed by the cyclin E, A, and B families [4]. Ordered CDK activity likewise governs progression through meiosis: chromosome condensation, congression, and alignment require a rise in cyclin B-CDK1 activity, then anaphase onset and chromosome segregation are driven by sudden inactivation of cyclin B-CDK1 by the anaphase promoting complex/ cyclosome (APC/C), an E3 ubiquitin ligase that targets substrates for degradation by the 26S proteasome [5]. Cyclin B-CDK1 activity re-accumulates following its depletion, but meiotic cells have the challenge of not inducing DNA replication during the period of low cyclin B-CDK1 activity between meiosis I and II [6,7]. The roles of specific cyclins in shaping CDK oscillations and thus in determining the orderly progression of meiosis remain poorly understood, particularly in mammalian oocytes.In this context, cyclin B3 is particularly enigmatic. Cyclin B3 belongs to a separate family with characteristics of both A-and B-type cyclins [8,9] and is evolutionarily conserved from early metazoans to human [10]. Ciona intestinalis cyclin B3 counteracts zyg...

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supporting

confidence: 79%

Cyclin B3 promotes APC/C activation and anaphase I onset in oocyte meiosis

Bouftas

Keeney

et al. 2018

Preprint

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“…Other sites of polyubiquitin chain formation have also been associated with various nondegradation-related cellular processes such as DNA repair (K6, K27, and K33), nuclear factor kB (NF-kB) signaling (M1), and post-Golgi trafficking of proteins (K33) (44 is that they are transferable, and the attachment of such sequence elements by means of genetic engineering confers instability on otherwise long-lived proteins (45). The degron itself is usually a short linear motif (46,47) A well-characterized example of an E3 ligase-degron pair is the degron in p53 and the E3 ligase MDM2 (murine double minute 2), which is a RING domain-containing individual E3 ligase (49). In the absence of DNA damage or other stress signals, MDM2 targets the constantly produced p53 for degradation.…”

Section: Alternative Consequences Of Ubiquitinationmentioning

confidence: 99%

Degrons in cancer

et al. 2017

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Degrons are the elements that are used by E3 ubiquitin ligases to target proteins for degradation. Most degrons are short linear motifs embedded within the sequences of modular proteins. As regulatory sites for protein abundance, they are important for many different cellular processes, such as progression through the cell cycle and monitoring cellular hypoxia. Degrons enable the elimination of proteins that are no longer required, preventing their possible dysfunction. Although the human genome encodes~600 E3 ubiquitin ligases, only a fraction of these enzymes have well-defined target degrons. Thus, for most cellular proteins, the destruction mechanisms are poorly understood. This is important for many diseases, especially for cancer, a disease that involves the enhanced expression of oncogenes and the persistence of encoded oncoproteins coupled with reduced abundance of tumor suppressors. Lossof-function mutations occur in the degrons of several oncoproteins, such as the transcription factors MYC and NRF2, and in various mitogenic receptors, such as NOTCH1 and several receptor tyrosine kinases. Mutations eliminating the function of the b-catenin degron are found in many cancers and are considered one of the most abundant mutations driving carcinogenesis. In this Review, we describe the current knowledge of degrons in cancer and suggest that increased research on the "dark degrome" (unknown degron-E3 relationships) would enhance progress in cancer research.

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“…Because of its crucial role in both completion of mitosis and maintenance of G1, numerous studies have dissected APC/C modes of action at the molecular level. Substrates are recognized through short, linear degron sequence motifs, termed D and KEN boxes, by APC/C co‐activator subunits Cdc20 and Cdh1/Fzr1 (He et al , ; Davey & Morgan, ). In humans, APC/C utilizes two E2‐conjugating enzymes, UBE2C/UbcH10 and UBE2S, to build polyubiquitin chains on substrates (Garnett et al , ; Williamson et al , ; Wu et al , ).…”

Section: Introductionmentioning

confidence: 99%

Cezanne/ OTUD 7B is a cell cycle‐regulated deubiquitinase that antagonizes the degradation of APC /C substrates

et al. 2018

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The anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase and key regulator of cell cycle progression. Since APC/C promotes the degradation of mitotic cyclins, it controls cell cycle-dependent oscillations in cyclin-dependent kinase (CDK) activity. Both CDKs and APC/C control a large number of substrates and are regulated by analogous mechanisms, including cofactor-dependent activation. However, whereas substrate dephosphorylation is known to counteract CDK, it remains largely unknown whether deubiquitinating enzymes (DUBs) antagonize APC/C substrate ubiquitination during mitosis. Here, we demonstrate that Cezanne/OTUD7B is a cell cycle-regulated DUB that opposes the ubiquitination of APC/C targets. Cezanne is remarkably specific for K11-linked ubiquitin chains, which are formed by APC/C in mitosis. Accordingly, Cezanne binds established APC/C substrates and reverses their APC/C-mediated ubiquitination. Cezanne depletion accelerates APC/C substrate degradation and causes errors in mitotic progression and formation of micronuclei. These data highlight the importance of tempered APC/C substrate destruction in maintaining chromosome stability. Furthermore, Cezanne is recurrently amplified and overexpressed in numerous malignancies, suggesting a potential role in genome maintenance and cancer cell proliferation.

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Building a Regulatory Network with Short Linear Sequence Motifs: Lessons from the Degrons of the Anaphase-Promoting Complex

Cited by 147 publications

References 98 publications

Cyclin B3 promotes APC/C activation and anaphase I onset in oocyte meiosis

Cyclin B3 promotes APC/C activation and anaphase I onset in oocyte meiosis

Degrons in cancer

Cezanne/ OTUD 7B is a cell cycle‐regulated deubiquitinase that antagonizes the degradation of APC /C substrates

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