Cell-division cycle protein 20 homologue (Cdc20) has important functions in chromosome segregation and mitotic exit. Cdc20 is the target of the spindle assembly checkpoint (SAC) and a key cofactor of the anaphase-promoting complex or cyclosome (APC/C) E3 ubiquitin ligase, thus regulating APC/C ubiquitin activity on specific substrates for their subsequent degradation by the proteasome. Here we discuss the roles of Cdc20 in SAC signalling and mitotic exit, describe how the integration of traditional approaches with emerging technologies has revealed new details of Cdc20 functions, comment about the potential of Cdc20 as a therapeutic target for the treatment of human malignancies, and discuss recent advances and controversies in the mechanistic understanding of the control of chromosome segregation during cell division.

The pandemic associated to Severe Acute Respiratory Syndrome Coronavirus type 2 (SARS-CoV-2) has resulted in a huge number of deaths and infected people. Although several vaccine programmes are currently underway and have reached phase 3, and a few small size drugs repurposed to aid treatment of severe cases of COVID-19 infections, effective therapeutic options for this disease do not currently exist. NSP16 is a S-adenosyl-L-Methionine (SAM) dependent 2′O-Methyltransferase that converts mRNA cap-0 into cap-1 structure to prevent virus detection by cell innate immunity mechanisms. NSP16 methylates the ribose 2′O-position of the first nucleotide of the mRNA only in the presence of an interacting partner, the protein NSP10. This feature suggests that inhibition of the NSP16 may represent a therapeutic window to treat COVID-19. To test this idea, we performed comparative structural analyses of the NSP16 present in human coronaviruses and developed a sinefungin (SFG) similarity-based virtual screening campaign to assess the druggability of the SARS-CoV-2 NSP16 enzyme. Through these studies, we identified the SFG analogue 44601604 as a promising more potent inhibitor of NSP16 to limit viral replication in infected cells, favouring viral clearance.

The mitotic spindle assembly checkpoint (SAC) is an intricate cell signaling system that ensures the high fidelity and timely segregation of chromosomes during cell division. Mistakes in this process can lead to the loss, gain, or rearrangement of the genetic material. Gross chromosomal aberrations are usually lethal but can cause birth and development defects as well as cancer. Despite advances in the identification of SAC protein components, important details of the interactions underpinning chromosome segregation regulation remain to be established. This review discusses the current understanding of the function, structure, mode of regulation, and dynamics of the assembly and disassembly of SAC subcomplexes, which ultimately safeguard the accurate transmission of a stable genome to descendants. We also discuss how diverse oncoviruses take control of human cell division by exploiting the SAC and the potential of this signaling circuitry as a pool of drug targets to develop effective cancer therapies.

Amyloid beta (Aβ), Adenovirus (Ad), Alzheimer's Disease (AD), Adriamycin (ADM), Acute Myeloid Leukemia (AML), Anaphase Promoting Complex/Cyclosome (APC/C), Adult T-cell leukaemia/lymphoma (ATL), Adenosine Triphosphate (ATP), Ataxia telangiectasia and Rad3-related protein (ATR), BRCA1-associated RING domain protein 1 (Bard1), Brain-Specific Kinase 2 (BRSK2), Budding uninhibited by benzimidazoles 1 (Bub1), Budding uninhibited by benzimidazoles 3 (Bub3), Budding uninhibited by benzimidazoles related 1 (BubR1), Chicken Anemia virus (CAV), Chicken Anemia Virus-Apoptin (CAV-Apoptin), Cyclic AMP response element binding protein (CBP), Cell division cycle 5 (Cdc5), Cell division cycle 6 protein (Cdc6), Cell Division Cycle 7 (Cdc7), Cell division cycle protein 20 (Cdc20), Cell division cycle protein 23 (Cdc23), Cell division cycle protein 26 (Cdc26), Cell division cycle protein 27 (Cdc27), Cell division control protein 42 (Cdc42), Cell Division Cycle 55 (Cdc55), Cadherin 1 (Cdh1), Cyclin-dependent kinase (Cdk), Cyclin-dependent kinase 1 (Cdk1), Cyclin-dependent kinase 4 (Cdk4), Cyclin-dependent kinase 5 (Cdk5), Chromatin licensing and DNA replication factor 1 (Cdt1), Centromere-associated protein E (CENP-E), Centromere-associated protein F (CENP-F), Checkpoint kinase 1 (Chk1), Chromosome instability and karyogamy protein 1 (Cik1), Casein kinase 1 (CK1), Casein kinase 1 delta (CK1δ), Cytoskeleton-associated protein 2 (CKAP2), Conditional Knockout (cKO), Cyclindependent kinases regulatory subunit 1 (Cks1), Central nervous system (CNS), Coimmunoprecipitation (co-IP), Chromosomal passenger complex (CPC), Cryogenic electron microscopy (cryo-EM), Destruction box (D-box), Damaged DNA binding protein 1 (DDB1), Cisplatin (DDP), Deoxyribonucleic acid (DNA), Deoxyribonucleotide triphosphate (dNTPS), Deoxythymidine triphosphate (dTTP) early (E), Adenovirus early region 1A (E1A), E2F Transcription Factor 1 (E2F1), E2F Transcription Factor 3 (E2F3), Early Region 4 Open Reading Frame 4 (E4orf4), Excitatory amino acid (EAA), Epithelial Cell Transforming 2 (Ect2), Euchromatic Histone Lysine Methyltransferase 2 (EHMT2), Electron microscopy (EM)Early mitotic inhibitor (Emi1), Endoplasmic Reticulum (ER), Eyes Absent 1 (EYA1), FANCD2-associated nuclease 1 (FAN1), Filaments in between nuclei protein 1 (Fin1), Forkhead box M1 (FoxM1), Fizzy-related protein homolog (Fzr), Gap 1 (G1), Gap 2 (G2), Glucose-6-phosphate dehydrogenase (G6PD), Granule cell progenitors (GCPs), Glucagonlike peptide (GLP), Glucagon-like peptide-1 (GLP1), Glutaminase 1 (GLS1), Glutamate receptor 1 (GluR1), glioblastoma stem-like cells (GSCs), Glutathione (GSH), Glutathione disulfide (GSSG), Human Adenovirus (HAd), Hepatitis B Virus (HBV), Hepatocellular carcinoma (HCC), Human cytomegalovirus (HCMV), Homologous to the E6-AP Carboxyl Terminus (HECT), Human Gyrovirus-Apoptin (HGyv-Apoptin), Hyaluronan-mediated motility

The Anaphase Promoting Complex (APC/C), a large cullin-RING E3-type ubiquitin ligase, constitutes the ultimate target of the Spindle Assembly Checkpoint (SAC), an intricate regulatory circuit that ensures the high fidelity of chromosome segregation in eukaryotic organisms by delaying the onset of anaphase until each chromosome is properly bi-oriented on the mitotic spindle. Cell-division cycle protein 20 homologue (CDC20) is a key regulator of APC/C function in mitosis. The formation of the APC/CCDC20 complex is required for the ubiquitination and degradation of select substrates, which is necessary to maintain the mitotic state. In contrast to the roles of CDC20 in animal species, little is known about CDC20 roles in the regulation of chromosome segregation in plants. Here we address this gap in knowledge and report the expression in insect cells; the biochemical and biophysical characterisation of Arabidopsis thaliana (AtCDC20) WD40 domain; and the nuclear and cytoplasmic distribution of full-length AtCDC20 when transiently expressed in tobacco plants. We also show that most AtCDC20 degrons share a high sequence similarity to other eukaryotes, arguing in favour of conserved degron functions in AtCDC20. However, important exceptions were noted such as the lack of a canonical MAD1 binding motif; a fully conserved RRY-box in all six AtCDC20 isoforms instead of a CRY-box motif, and low conservation of key residues known to be phosphorylated by BUB1 and PLK1 in other species to ensure a robust SAC response. Taken together, our studies provide insights into AtCDC20 structure and function and the evolution of SAC signalling in plants.