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Anaphase-promoting complex

Karolin Eifler, Sabine A G Cuijpers, Edwin Willemstein, Jonne A Raaijmakers, Dris El Atmioui, Huib Ovaa, René H Medema, Alfred C O Vertegaal
Signal transduction by small ubiquitin-like modifier (SUMO) regulates a myriad of nuclear processes. Here we report on the role of SUMO in mitosis in human cell lines. Knocking down the SUMO conjugation machinery results in a delay in mitosis and defects in mitotic chromosome separation. Searching for relevant SUMOylated proteins in mitosis, we identify the anaphase-promoting complex/cyclosome (APC/C), a master regulator of metaphase to anaphase transition. The APC4 subunit is the major SUMO target in the complex, containing SUMO acceptor lysines at positions 772 and 798...
March 16, 2018: Nature Communications
Ling Shih Quek, Nicolas Grasset, Joanita Binte Jasmen, Kim S Robinson, Sophie Bellanger
Cdc20 and Cdh1 activate the Anaphase Promoting Complex/Cyclosome (APC/C), a master cell cycle regulator. Although cell cycle modifications occur during differentiation of stem cells, a role for the APC/C on stem cell fate has not been established in embryonic or adult human tissues. We found that differentiated human primary keratinocytes (HPKs) from the skin express extremely low levels of Cdc20 compared to HPK stem cells (holoclones). In agreement with this, staining of human skin biopsies showed that Cdc20 is expressed in occasional cells from the basal and epibasal layers of the epidermis and is absent from the differentiated layers...
March 8, 2018: Journal of Investigative Dermatology
Christine C Lee, Bing Li, Hongtao Yu, Michael J Matunis
The Anaphase Promoting Complex/Cyclosome (APC/C) is a ubiquitin E3 ligase that functions as the gatekeeper to mitotic exit. APC/C activity is controlled by an interplay of multiple pathways during mitosis, including the spindle assembly checkpoint (SAC), that are not yet fully understood. Here, we show that sumoylation of the APC4 subunit of the APC/C peaks during mitosis and is critical for timely APC/C activation and anaphase onset. We have also identified a functionally important SUMO interacting motif in the cullin-homology domain of APC2 located near the APC4 sumoylation sites and APC/C catalytic core...
March 8, 2018: ELife
Gah-Hyun Lim, Timothy Hoey, Shifeng Zhu, Marion Clavel, Keshun Yu, Duroy Navarre, Aardra Kachroo, Jean-Marc Deragon, Pradeep Kachroo
The E3 ubiquitin ligase COP1 (Constitutive Photomorphogenesis 1) is a well known component of the light-mediated plant development that acts as a repressor of photomorphogenesis. Here we show that COP1 positively regulates defense against turnip crinkle virus (TCV) and avrRPM1 bacteria by contributing to stability of resistance (R) protein HRT and RPM1, respectively. HRT and RPM1 levels and thereby pathogen resistance is significantly reduced in the cop1 mutant background. Notably, the levels of at least two double-stranded RNA binding (DRB) proteins DRB1 and DRB4 are reduced in the cop1 mutant background suggesting that COP1 affects HRT stability via its effect on the DRB proteins...
March 7, 2018: PLoS Pathogens
Sabine A G Cuijpers, Alfred C O Vertegaal
Cell division is tightly regulated to disentangle copied chromosomes in an orderly manner and prevent loss of genome integrity. During mitosis, transcriptional activity is limited and post-translational modifications (PTMs) are responsible for functional protein regulation. Essential mitotic regulators, including polo-like kinase 1 (PLK1) and cyclin-dependent kinases (CDK), as well as the anaphase-promoting complex/cyclosome (APC/C), are members of the enzymatic machinery responsible for protein modification...
February 24, 2018: Trends in Biochemical Sciences
Nuria Ferrandiz, Consuelo Barroso, Oana Telecan, Nan Shao, Hyun-Min Kim, Sarah Testori, Peter Faull, Pedro Cutillas, Ambrosious P Snijders, Monica P Colaiácovo, Enrique Martinez-Perez
The formation of haploid gametes from diploid germ cells requires the regulated two-step release of sister chromatid cohesion (SCC) during the meiotic divisions. Here, we show that phosphorylation of cohesin subunit REC-8 by Aurora B promotes SCC release at anaphase I onset in C. elegans oocytes. Aurora B loading to chromatin displaying Haspin-mediated H3 T3 phosphorylation induces spatially restricted REC-8 phosphorylation, preventing full SCC release during anaphase I. H3 T3 phosphorylation is locally antagonized by protein phosphatase 1, which is recruited to chromosomes by HTP-1/2 and LAB-1...
February 26, 2018: Nature Communications
Deyanira Guadalupe Acuña-Hernández, Laura Arreola-Mendoza, Ramsés Santacruz-Márquez, Sihomara Patricia García-Zepeda, Lyda Yuliana Parra-Forero, Jesús Alberto Olivares-Reyes, Isabel Hernández-Ochoa
In ovarian follicles, cumulus cells communicate with the oocyte through gap junction intercellular communication (GJIC), to nurture the oocyte and control its meiosis arrest and division. Bisphenol A (BPA) is a monomer found in polycarbonate-made containers that can induce functional alterations, including impaired oocyte meiotic division and reduced molecule transfer in GJIC. However, how BPA alters oocyte meiotic division is unclear. We investigated whether BPA effects on oocyte meiotic division were correlated with reduced transfer in GJIC...
February 16, 2018: Toxicology and Applied Pharmacology
Shukun Luo, Liang Tong
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). Here we review recent structures of the active protease segment of Chaetomium thermophilum separase in complex with a substrate-mimic inhibitor and full-length Saccharomyces cerevisiae and Caenorhabditis elegans separase in complex with securin...
February 13, 2018: Current Opinion in Structural Biology
Carmen Morales, Ana Losada
Replicated chromatids are held together from the time they emerge from the replication fork until their separation in anaphase. This process, known as cohesion, promotes faithful DNA repair by homologous recombination in interphase and ensures accurate chromosome segregation in mitosis. Identification of cohesin thirty years ago solved a long-standing question about the nature of the linkage keeping together the sister chromatids. Cohesin is an evolutionarily conserved complex composed of a heterodimer of the Structural Maintenance of Chromosomes (SMC) family of ATPases, Smc1 and Smc3, the kleisin subunit Rad21 and a Huntingtin/EF3/PP2A/Tor1 (HEAT) repeat domain-containing subunit named SA/STAG...
February 9, 2018: Current Opinion in Cell Biology
Danielle Sitry-Shevah, Sharon Kaisari, Adar Teichner, Shirly Miniowitz-Shemtov, Avram Hershko
The mitotic checkpoint system ensures the fidelity of chromosome segregation in mitosis by preventing premature initiation of anaphase until correct bipolar attachment of chromosomes to the mitotic spindle is reached. It promotes the assembly of a mitotic checkpoint complex (MCC), composed of BubR1, Bub3, Cdc20, and Mad2, which inhibits the activity of the anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase. When the checkpoint is satisfied, anaphase is initiated by the disassembly of MCC. Previous studies indicated that the dissociation of APC/C-bound MCC requires ubiquitylation and suggested that the target of ubiquitylation is the Cdc20 component of MCC...
February 5, 2018: Proceedings of the National Academy of Sciences of the United States of America
Hoi Tang Ma, Randy Y C Poon
The spindle assembly checkpoint (SAC) prevents premature segregation of chromosomes during mitosis. This process requires structural remodeling of MAD2 from O-MAD2 to C-MAD2 conformation. After the checkpoint is satisfied, C-MAD2 is reverted to O-MAD2 to allow anaphase-promoting complex/cyclosome (APC/C) to trigger anaphase. Recently, the AAA+-ATPase TRIP13 was shown to act in concert with p31comet to catalyze C- to O-MAD2. Paradoxically, although C-MAD2 is present in TRIP13-deficient cells, the SAC cannot be activated...
February 6, 2018: Cell Reports
Lingyun Liu, Kaimin Guo, Zuowen Liang, Fubiao Li, Hongliang Wang
To screen for marker genes associated with to the metastasis of prostate cancer (PCa), in silico analysis of the Gene Expression Omnibus dataset GSE27616, which included 4 metastatic and 5 localized PCa tissue samples, was performed. Differentially expressed genes (DEGs) were identified. Their potential functions were identified by Gene Ontology and Kyoto Encyclopedia of Gene Genomes pathway enrichment analyses. Furthermore, protein-protein interaction (PPI) networks for DEGs were constructed using Cytoscape...
January 2018: Oncology Letters
Helen Chen, Marisa Connell, Lin Mei, Gregor S D Reid, Christopher A Maxwell
Mitotic spindle assembly and organization require forces generated by motor proteins. The activity of these motors is regulated by non-motor adaptor proteins. However, there are limited studies reporting the functional importance of adaptors on the balance of motor forces and the promotion of faithful and timely cell division. Here, we show that genomic deletion or siRNA silencing of the non-motor adaptor Hmmr/HMMR disturbs spindle microtubule organization and bipolar chromosome-kinetochore attachments with a consequent elevated occurrence of aneuploidy...
January 31, 2018: Molecular Biology of the Cell
K L Thu, J Silvester, M J Elliott, W Ba-Alawi, M H Duncan, A C Elia, A S Mer, P Smirnov, Z Safikhani, B Haibe-Kains, T W Mak, D W Cescon
TTK protein kinase (TTK), also known as Monopolar spindle 1 (MPS1), is a key regulator of the spindle assembly checkpoint (SAC), which functions to maintain genomic integrity. TTK has emerged as a promising therapeutic target in human cancers, including triple-negative breast cancer (TNBC). Several TTK inhibitors (TTKis) are being evaluated in clinical trials, and an understanding of the mechanisms mediating TTKi sensitivity and resistance could inform the successful development of this class of agents. We evaluated the cellular effects of the potent clinical TTKi CFI-402257 in TNBC models...
January 29, 2018: Proceedings of the National Academy of Sciences of the United States of America
Kenneth C Atkins, Frederick Cross
The cyclin-dependent kinase CDK1 is essential for mitosis in fungi and animals. Plant genomes contain the CDK1 ortholog CDKA, and a plant kingdom-specific relative, CDKB. The green alga Chlamydomonas reinhardtii has a long G1 growth period followed by rapid cycles of DNA replication and cell division. We show that null alleles of CDKA extend the growth period prior to the first division cycle and modestly extend the subsequent division cycles, but do not prevent cell division, indicating at most a minor role for the CDK1 ortholog in mitosis in Chlamydomonas...
January 24, 2018: Plant Cell
Eleni Petsalaki, Maria Dandoulaki, George Zachos
The mitotic spindle checkpoint delays anaphase onset in the presence of unattached kinetochores, and efficient checkpoint signaling requires kinetochore localization of the Rod-ZW10-Zwilch (RZZ) complex. In the present study, we show that human Chmp4c, a protein involved in membrane remodeling, localizes to kinetochores in prometaphase but is reduced in chromosomes aligned at the metaphase plate. Chmp4c promotes stable kinetochore-microtubule attachments and is required for proper mitotic progression, faithful chromosome alignment, and segregation...
January 23, 2018: Journal of Cell Biology
Stephen C West, Ying Wai Chan
The efficient processing of homologous recombination (HR) intermediates, which often contain four-way structures known as Holliday junctions (HJs), is required for proper chromosome segregation at mitosis. Eukaryotic cells possess three distinct pathways of resolution: (i) HJ dissolution mediated by BLM-topoisomerase IIIα-RMI1-RMI2 (BTR) complex, and HJ resolution catalyzed by either (ii) SLX1-SLX4-MUS81-EME1-XPF-ERCC1 (SMX complex) or (iii) GEN1. The BTR pathway acts at all times throughout the cell cycle, whereas the actions of SMX and GEN1 are restrained in S phase and become elevated late in the cell cycle to ensure the resolution of persistent recombination intermediates before mitotic division...
January 18, 2018: Cold Spring Harbor Symposia on Quantitative Biology
Srinadh Choppara, Sunil K Malonia, Ganga Sankaran, Michael R Green, Manas Kumar Santra
The F-box protein FBXO31 is a tumor suppressor that is encoded in 16q24.3, for which there is loss of heterozygosity in various solid tumors. FBXO31 serves as the substrate-recognition component of the SKP/Cullin/F-box protein class of E3 ubiquitin ligases and has been shown to direct degradation of pivotal cell-cycle regulatory proteins including cyclin D1 and the p53 antagonist MDM2. FBXO31 levels are normally low but increase substantially following genotoxic stress through a mechanism that remains to be determined...
January 17, 2018: Proceedings of the National Academy of Sciences of the United States of America
Alka Sharma, Meenakshi Tiwari, Anumegha Gupta, Ashutosh N Pandey, Pramod K Yadav, Shail K Chaube
In mammals, journey from metaphase-I (M-I) to metaphase-II (M-II) is important since oocyte extrude first polar body (PB-I) and gets converted into haploid gamete. The molecular and cellular changes associated with meiotic cell cycle progression from M-I to M-II stage and extrusion of PB-I remain ill understood. Several factors drive oocyte meiosis from M-I to M-II stage. The mitogen-activated protein kinase3/1 (MAPK3/1), signal molecules and Rho family GTPases act through various pathways to drive cell cycle progression from M-I to M-II stage...
January 13, 2018: Journal of Cellular Physiology
Lingwei Li, Liqing Fan, Nanni Peng, Lihua Yang, Lisha Mou, Weiren Huang
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. The mRNA levels of securin, cyclin B, cyclin dependent kinase 1 (CDK1), and cyclin dependent kinase 2 (CDK2), which are all targeted for destruction via the anaphase-promoting complex/cyclosomeCDC20 (APC/CCDC20) pathway, were detected at relatively high levels using real-time quantitative polymerase chain reaction analysis...
November 21, 2017: Oncotarget
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