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EMBO J 2021 Apr 1;40(7):e106812. Epub 2021 Mar 1.

Laboratory of Chromosome Biology, Max Planck Institute of Biochemistry, Martinsried, Germany.

Genome haploidization involves sequential loss of cohesin from chromosome arms and centromeres during two meiotic divisions. At centromeres, cohesin's Rec8 subunit is protected from separase cleavage at meiosis I and then deprotected to allow its cleavage at meiosis II. Protection of centromeric cohesin by shugoshin-PP2A seems evolutionarily conserved. Read More

Elife 2020 09 1;9. Epub 2020 Sep 1.

Department of Biochemistry, University of Oxford, Oxford, United Kingdom.

APC/C-mediated proteolysis of cyclin B and securin promotes anaphase entry, inactivating CDK1 and permitting chromosome segregation, respectively. Reduction of CDK1 activity relieves inhibition of the CDK1-counteracting phosphatases PP1 and PP2A-B55, allowing wide-spread dephosphorylation of substrates. Meanwhile, continued APC/C activity promotes proteolysis of other mitotic regulators. Read More

Mol Biol Cell 2020 10 5;31(21):2315-2330. Epub 2020 Aug 5.

Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK.

Ubiquitin-dependent proteolysis of cyclin B and securin initiates sister chromatid segregation and anaphase. The anaphase-promoting complex/cyclosome and its coactivator CDC20 (APC/C) form the main ubiquitin E3 ligase for these two proteins. APC/C is regulated by CDK1-cyclin B and counteracting PP1 and PP2A family phosphatases through modulation of both activating and inhibitory phosphorylation. Read More

Nucleic Acids Res 2020 06;48(11):6092-6107

Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Proteos, 61 Biopolis Drive, Singapore.

The DNA damage checkpoint halts cell cycle progression in G2 in response to genotoxic insults. Central to the execution of cell cycle arrest is the checkpoint-induced stabilization of securin-separase complex (yeast Pds1-Esp1). The checkpoint kinases Chk1 and Chk2 (yeast Chk1 and Rad53) are thought to critically contribute to the stability of securin-separase complex by phosphorylation of securin, rendering it resistant to proteolytic destruction by the anaphase promoting complex (APC). Read More

Nature 2020 04 8;580(7804):536-541. Epub 2020 Apr 8.

Chair of Genetics, University of Bayreuth, Bayreuth, Germany.

Separation of eukaryotic sister chromatids during the cell cycle is timed by the spindle assembly checkpoint (SAC) and ultimately triggered when separase cleaves cohesion-mediating cohesin. Silencing of the SAC during metaphase activates the ubiquitin ligase APC/C (anaphase-promoting complex, also known as the cyclosome) and results in the proteasomal destruction of the separase inhibitor securin. In the absence of securin, mammalian chromosomes still segregate on schedule, but it is unclear how separase is regulated under these conditions. Read More

Development 2019 12 2;146(23). Epub 2019 Dec 2.

State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 100101 Beijing, China

Chromosome segregation is driven by separase, activity of which is inhibited by binding to securin and cyclin B1/CDK1. In meiosis, premature separase activity will induce aneuploidy or abolish chromosome segregation owing to the untimely destruction of cohesin. Recently, we have proved that cyclin B2 can compensate for cyclin B1 in CDK1 activation for the oocyte meiosis G2/M transition. Read More

FEBS Lett 2019 10 18;593(20):2908-2924. Epub 2019 Sep 18.

Department of Biochemistry, University of Oxford, UK.

Here, we will review the evidence showing that mitotic exit is initiated by regulated proteolysis and then driven by the PPP family of phosphoserine/threonine phosphatases. Rapid APC/C and ubiquitin-dependent proteolysis of cyclin B and securin initiates sister chromatid separation, the first step of mitotic exit. Because proteolysis of Aurora and Polo family kinases dependent on APC/C is relatively slow, this creates a new regulatory state, anaphase, different to G2 and M-phase. Read More

J Cell Sci 2019 09 26;132(18). Epub 2019 Sep 26.

The Christopher Chen Oocyte Biology Research Laboratory, UQ Centre for Clinical Research, The University of Queensland, Herston 4029, QLD, Australia

During mitosis, anaphase is triggered by anaphase-promoting complex (APC)-mediated destruction of securin and cyclin B1, which leads to inactivation of cyclin-dependent kinase 1 (Cdk1). By regulating APC activity, the mitotic spindle assembly checkpoint (SAC) therefore has robust control over anaphase timing to prevent chromosome mis-segregation. Mammalian oocytes are prone to aneuploidy, the reasons for which remain obscure. Read More

Curr Opin Struct Biol 2018 04 14;49:114-122. Epub 2018 Feb 14.

Department of Biological Sciences Columbia University New York, NY 10027, USA. Electronic address:

The cysteine protease separase opens the cohesin ring by cleaving its kleisin subunit and is a pivotal cell cycle factor for the transition from metaphase to anaphase. It is inhibited by forming a complex with the chaperone securin, and in vertebrates, also by the Cdk1-cyclin B1 complex. Separase is activated upon the destruction of securin or cyclin B1 by the proteasome, after ubiquitination by the anaphase-promoting complex/cyclosome (APC/C). Read More

Oncotarget 2017 Nov 16;8(59):99816-99824. Epub 2017 Sep 16.

Key Laboratory of Medical Reprogramming Technology, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Guangdong 518035, China.

Idiopathic azoospermia (IA) is a severe form of male infertility due to unknown causes. To investigate relative gene expression in human idiopathic non-obstructive azoospermia, we sequenced all the exons of cell division cycle 20 (CDC20) in 766 patients diagnosed with IA, as well as in 521 normally fertile men. Three novel missense mutations (S72G, R322Q, R383C) of CDC20 were detected and further confirmed by Sanger sequencing. Read More

Cold Spring Harb Symp Quant Biol 2017 13;82:111-121. Epub 2017 Nov 13.

Ludwig Institute for Cancer Research, La Jolla, California 92093.

The anaphase-promoting complex/cyclosome (APC/C) is a large multisubunit ubiquitin ligase that triggers the metaphase-to-anaphase transition in the cell cycle by targeting the substrates cyclin B and securin for destruction. APC/C activity toward these two key substrates requires the coactivator Cdc20. To ensure that cells enter mitosis and partition their duplicated genome with high accuracy, APC/C activity must be tightly controlled. Read More

Nat Commun 2017 05 18;8:15346. Epub 2017 May 18.

Development and Stem Cells Program, Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia.

Sister chromatid attachment during meiosis II (MII) is maintained by securin-mediated inhibition of separase. In maternal ageing, oocytes show increased inter-sister kinetochore distance and premature sister chromatid separation (PSCS), suggesting aberrant separase activity. Here, we find that MII oocytes from aged mice have less securin than oocytes from young mice and that this reduction is mediated by increased destruction by the anaphase promoting complex/cyclosome (APC/C) during meiosis I (MI) exit. Read More

Curr Biol 2017 Jan 22;27(1):137-143. Epub 2016 Dec 22.

Wellcome Trust Centre for Cell Biology, University of Edinburgh King's Buildings, Max Born Crescent, Edinburgh EH9 3BF, UK. Electronic address:

The spindle checkpoint acts as a mitotic surveillance system, monitoring interactions between kinetochores and spindle microtubules and ensuring high-fidelity chromosome segregation [1-3]. The checkpoint is activated by unattached kinetochores, and Mps1 kinase phosphorylates KNL1 on conserved MELT motifs to generate a binding site for the Bub3-Bub1 complex [4-7]. This leads to dynamic kinetochore recruitment of Mad proteins [8, 9], a conformational change in Mad2 [10-12], and formation of the mitotic checkpoint complex (MCC: Cdc20-Mad3-Mad2 [13-15]). Read More

Cell Cycle 2016 07 10;15(14):1811. Epub 2016 May 10.

b Department of Genetics , Cell Biology and Development, University of Minnesota , Minneapolis , MN , USA.

J Cell Sci 2016 Feb 16;129(3):531-42. Epub 2015 Dec 16.

Department of Biological Sciences, University of Windsor, Windsor, Ontario, Canada N9B 2P1

Chromosome segregation in meiosis is controlled by a conserved pathway that culminates in Separase-mediated cleavage of the α-kleisin Rec8, leading to dissolution of cohesin rings. Drosophila has no gene encoding Rec8, and the absence of a known Separase target raises the question of whether Separase and its regulator Securin (Pim in Drosophila) are important in Drosophila meiosis. Here, we investigate the role of Securin, Separase and the cohesin complex in female meiosis using fluorescence in situ hybridization against centromeric and arm-specific sequences to monitor cohesion. Read More

Cell Mol Life Sci 2016 Mar 9;73(5):949-60. Epub 2015 Dec 9.

Department of Medical Oncology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Proper cell cycle progression is safeguarded by the oscillating activities of cyclin/cyclin-dependent kinase complexes. An important player in the regulation of mitotic cyclins is the anaphase-promoting complex/cyclosome (APC/C), a multi-subunit E3 ubiquitin ligase. Prior to entry into mitosis, the APC/C remains inactive, which allows the accumulation of mitotic regulators. Read More

Biol Open 2015 Mar 6;4(4):484-95. Epub 2015 Mar 6.

Division of Cell Biology I (B5) and Division of Molecular Carcinogenesis (B7), The Netherlands Cancer Institute (NKI-AvL), Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands Section of Oncogenetics, Department of Clinical Genetics and CCA/V-ICI Research Program Oncogenesis, VUmc Medical Faculty, van de Boechorststraat 7, 1081 BT Amsterdam, The Netherlands

When cells enter mitosis, the anaphase-promoting complex/cyclosome (APC/C) is activated by phosphorylation and binding of Cdc20. The RXXL destruction box (D-box) of cyclin B1 only binds Cdc20 after release of the spindle checkpoint in metaphase, initiating cyclin B1 ubiquitination upon chromosome bi-orientation. However, we found that cyclin B1, through Cdk1 and Cks, is targeted to the phosphorylated APC/C(Cdc20) at the start of prometaphase, when the spindle checkpoint is still active. Read More

Biochem Soc Trans 2015 Feb;43(1):19-22

*Division of Biomedical Cell Biology, Warwick Medical School, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, U.K.

The segregation of sister chromatids during mitosis is one of the most easily visualized, yet most remarkable, events during the life cycle of a cell. The accuracy of this process is essential to maintain ploidy during cell duplication. Over the past 20 years, substantial progress has been made in identifying components of both the kinetochore and the mitotic spindle that generate the force to move mitotic chromosomes. Read More

J Cell Biol 2014 Oct 6;207(1):23-39. Epub 2014 Oct 6.

Department of Physiology and Department of Biochemistry and Biophysics and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158

The ubiquitin protein ligase anaphase-promoting complex or cyclosome (APC/C) controls mitosis by promoting ordered degradation of securin, cyclins, and other proteins. The mechanisms underlying the timing of APC/C substrate degradation are poorly understood. We explored these mechanisms using quantitative fluorescence microscopy of GFP-tagged APC/C(Cdc20) substrates in living budding yeast cells. Read More

Nature 2014 Oct 24;514(7524):646-9. Epub 2014 Aug 24.

Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA.

Protein machines are multi-subunit protein complexes that orchestrate highly regulated biochemical tasks. An example is the anaphase-promoting complex/cyclosome (APC/C), a 13-subunit ubiquitin ligase that initiates the metaphase-anaphase transition and mitotic exit by targeting proteins such as securin and cyclin B1 for ubiquitin-dependent destruction by the proteasome. Because blocking mitotic exit is an effective approach for inducing tumour cell death, the APC/C represents a potential novel target for cancer therapy. Read More

Curr Biol 2014 Jul 12;24(13):1556-62. Epub 2014 Jun 12.

Department of Physiology, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address:

The anaphase-promoting complex/cyclosome (APC/C) is a protein-ubiquitin ligase (E3) that initiates the final events of mitosis by catalyzing the ubiquitination and proteasomal destruction of securin, cyclins, and other substrates [1, 2]. Like other members of the RING family of E3s [3, 4], the APC/C catalyzes direct ubiquitin transfer from an E2-ubiquitin conjugate (E2-Ub) to lysine residues on the protein substrate. The APC/C is activated at specific cell-cycle stages by association with an activator subunit, Cdc20 or Cdh1, which provides binding sites for specific substrate sequence motifs, or degrons. Read More

Curr Biol 2014 Mar 27;24(6):638-45. Epub 2014 Feb 27.

Cell Division and Aneuploidy Laboratory, Cancer Research UK London Research Institute, Clare Hall Laboratories, Blanche Lane, South Mimms, Hertfordshire EN6 3LD, UK. Electronic address:

Two mechanisms safeguard the bipolar attachment of chromosomes in mitosis. A correction mechanism destabilizes erroneous attachments that do not generate tension across sister kinetochores [1]. In response to unattached kinetochores, the mitotic checkpoint delays anaphase onset by inhibiting the anaphase-promoting complex/cyclosome (APC/C(Cdc20)) [2]. Read More

Int J Biochem Cell Biol 2014 Feb 17;47:113-7. Epub 2013 Dec 17.

School of Science and Health, The University of Western Sydney, Australia; Central Clinical School and Bosch Institute, The University of Sydney and Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, Australia. Electronic address:

The ubiquitin-conjugating enzymes 2C (UBE2C) is an integral component of the ubiquitin proteasome system. UBE2C consists of a conserved core domain containing the catalytic Cys residue and an N-terminal extension. The core domain is required for ubiquitin adduct formation by interacting with the ubiquitin-fold domain in the E1 enzyme, and contributes to the E3 enzyme binding. Read More

Springerplus 2013 25;2:562. Epub 2013 Oct 25.

Radiation Biology Center, Kyoto University, Yoshida-Konoe cho, Sakyo ku, Kyoto, Japan.

Mad2 is a key component of the spindle assembly checkpoint (SAC) that delays the onset of anaphase until all kinetochores are attached to the spindle. It binds to Cdc20 and prevents it from promoting destruction of an anaphase inhibitor, Securin. Previously, we showed that a Mad2-binding protein, p31(comet), formed a complex with Mad2 upon the completion of spindle attachment. Read More

J Cell Biol 2013 Oct 7;203(1):87-100. Epub 2013 Oct 7.

Medical Research Council Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, England, UK.

The switch from activation of the anaphase-promoting complex/cyclosome (APC/C) by CDC20 to CDH1 during anaphase is crucial for accurate mitosis. APC/C(CDC20) ubiquitinates a limited set of substrates for subsequent degradation, including Cyclin B1 and Securin, whereas APC/C(CDH1) has a broader specificity. This switch depends on dephosphorylation of CDH1 and the APC/C, and on the degradation of CDC20. Read More

Dev Cell 2013 Apr 28;25(1):43-54. Epub 2013 Mar 28.

Mammalian Oocyte and Embryo Research Laboratory, Cell and Developmental Biology, UCL, London WC1E 6BT, UK.

The functions of the Ndc80/Hec1 subunit of the highly conserved Ndc80 kinetochore complex are normally restricted to M phase when it exerts a pivotal kinetochore-based role. Here, we find that in mouse oocytes, depletion of Hec1 severely compromises the G2-M transition because of impaired activation of cyclin-dependent kinase 1 (Cdk1). Unexpectedly, impaired M phase entry is due to instability of the Cdk1-activating subunit, cyclin B2, which cannot be covered by cyclin B1. Read More

Proc Natl Acad Sci U S A 2012 Nov 22;109(45):18419-24. Epub 2012 Oct 22.

Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

The anaphase-promoting complex/cyclosome (APC/C) promotes anaphase onset and mitotic exit through ubiquitinating securin and cyclin B1. The mitotic APC/C activator, the cell division cycle 20 (Cdc20) protein, directly interacts with APC/C degrons--the destruction (D) and KEN boxes. APC/C(Cdc20) is the target of the spindle checkpoint. Read More

J Vis Exp 2012 Jun 14(64):e3763. Epub 2012 Jun 14.

Institute for Cell and Molecular Biosciences, University of Newcastle, United Kingdom.

The spindle assembly checkpoint (SAC) mechanism is an active signal, which monitors the interaction between chromosome kinetochores and spindle microtubules to prevent anaphase onset until the chromosomes are properly connected. Cells use this mechanism to prevent aneuploidy or genomic instability, and hence cancers and other human diseases like birth defects and Alzheimer's. A number of the SAC components such as Mad1, Mad2, Bub1, BubR1, Bub3, Mps1, Zw10, Rod and Aurora B kinase have been identified and they are all kinetochore dynamic proteins. Read More

Development 2012 Jun 18;139(11):1941-6. Epub 2012 Apr 18.

Cell and Developmental Biology, University College London, London WC1E 6BT, UK.

The spindle assembly checkpoint (SAC) averts aneuploidy by coordinating proper bipolar chromosomal attachment with anaphase-promoting complex/cyclosome (APC/C)-mediated securin and cyclin B1 destruction required for anaphase onset. The generation of a Mad2-based signal at kinetochores is central to current models of SAC-based APC/C inhibition. During mitosis, kinetochores of polar-displaced chromosomes, which are at greatest risk of mis-segregating, recruit the highest levels of Mad2, thereby ensuring that SAC activation is proportionate to aneuploidy risk. Read More

Nat Cell Biol 2012 Jan 29;14(2):168-76. Epub 2012 Jan 29.

Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA.

The anaphase-promoting complex or cyclosome (APC/C) initiates mitotic exit by ubiquitylating cell-cycle regulators such as cyclin B1 and securin. Lys 48-linked ubiquitin chains represent the canonical signal targeting proteins for degradation by the proteasome, but they are not required for the degradation of cyclin B1. Lys 11-linked ubiquitin chains have been implicated in degradation of APC/C substrates, but the Lys 11-chain-forming E2 UBE2S is not essential for mitotic exit, raising questions about the nature of the ubiquitin signal that targets APC/C substrates for degradation. Read More