The C-terminal disordered loop domain of Apc8 unlocks APC/C mitotic activation.

The anaphase-promoting complex/cyclosome (APC/C) is a critical and tightly regulated E3 ligase that orchestrates the cellular life cycle by controlling the degradation of cell cycle regulators. An intriguing feature of this complex is an autoinhibition mechanism: an intrinsically disordered loop domain, Apc1-300L, blocks Cdc20 coactivator binding, yet phosphorylation of Apc1-300L counteracts this autoinhibition. Many such disordered loops within APC/C remain unexplored. Our systematic analysis of loop-deficient APC/C mutants uncovered a pivotal role for Apc8's C-terminal loop (Apc8-L) in mitotic activation. Apc8-L directly recruits the CDK adaptor protein, Xe-p9/Cks2, positioning the Xe-p9-CDK-CycB complex near Apc1-300L. This stimulates the phosphorylation and removal of Apc1-300L, prompting the formation of active APC/CCdc20. Strikingly, without both Apc8-L and Apc3-L, the APC/C is rendered inactive during mitosis, highlighting Apc8-L's synergistic role with other loops and kinases. This study broadens our understanding of the intricate dynamics in APC/C regulation and provides insights on the regulation of macromolecular complexes.

GhAPC8 regulates leaf blade angle by modulating multiple hormones in cotton (Gossypium hirsutum L.).

Leaf angle, including leaf petiole angle (LPA) and leaf blade angle (LBA), is an important trait affecting plant architecture. Anaphase-promoting complex/cyclosome (APC/C) genes play a vital role in plant growth and development, including regulation of leaf angle. Here, we identified and characterized the APC genes in Upland cotton (G. hirsutum L.) with a focus on GhAPC8, a homolog of soybean GmILPA1 involved in regulation of LPA. We showed that independently silencing the At or Dt sub-genome homoeolog of GhAPC8 using virus-induced gene silencing reduced plant height and LBA, and that reduction of LBA could be caused by uneven growth of cortex parenchyma cells on the adaxial and abaxial sides of the junction between leaf blade and leaf petiole. The junction between leaf blade and leaf petiole of the GhAPC8-silenced plants had an elevated level of brassinosteroid (BR) and a decreased levels of auxin and gibberellin. Consistently, comparative transcriptome analysis found that silencing GhAPC8 activated genes of the BR biosynthesis and signaling pathways as well as genes related to ubiquitin-mediated proteolysis. Weighted gene co-expression network analysis (WGCNA) identified gene modules significantly associated with plant height and LBA, and candidate genes bridging GhAPC8, the pathways of BR biosynthesis and signaling and ubiquitin-mediated proteolysis. These results demonstrated a role of GhAPC8 in regulating LBA, likely achieved by modulating the accumulation and signaling of multiple phytohormones.

Cell division cycle 23 is required for mouse oocyte meiotic maturation.

Precise regulation of chromosome segregation during oocyte meiosis is of vital importance to mammalian reproduction. Anaphase promoting complex/cyclosome (APC/C) is reported to play an important role in metaphase-to-anaphase transition. Here we report that cell division cycle 23 (Cdc23, also known as APC8) plays a critical role in regulating the oocyte chromosome separation. Cdc23 localized on the meiotic spindle, and microinjection of Cdc23 siRNA caused decreased ratios of metaphase-to-anaphase transition. Loss of Cdc23 resulted in abnormal spindles, misaligned chromosomes, errors of homologous chromosome segregation, and production of aneuploid oocytes. Further study showed that inactivation of spindle assembly checkpoint and degradation of Cyclin B1 and securin were disturbed after Cdc23 knockdown. Furthermore, we found that inhibiting spindle assembly checkpoint protein Msp1 partly rescued the decreased polar body extrusion and reduced the accumulation of securin in Cdc23 knockdown oocytes. Taken together, our data demonstrate that Cdc23 is required for the chromosome segregation through regulating the spindle assembly checkpoint activity, and cyclin B1 and securin degradation in meiotic mouse oocytes.

The Arabidopsis anaphase-promoting complex/cyclosome subunit 8 is required for male meiosis.

Faithful chromosome segregation is required for both mitotic and meiotic cell divisions and is regulated by multiple mechanisms including the anaphase-promoting complex/cyclosome (APC/C), which is the largest known E3 ubiquitin-ligase complex and has been implicated in regulating chromosome segregation in both mitosis and meiosis in animals. However, the role of the APC/C during plant meiosis remains largely unknown. Here, we show that Arabidopsis APC8 is required for male meiosis. We used a combination of genetic analyses, cytology and immunolocalisation to define the function of AtAPC8 in male meiosis. Meiocytes from apc8-1 plants exhibit several meiotic defects including improper alignment of bivalents at metaphase I, unequal chromosome segregation during anaphase II, and subsequent formation of polyads. Immunolocalisation using an antitubulin antibody showed that APC8 is required for normal spindle morphology. We also observed mitotic defects in apc8-1, including abnormal sister chromatid segregation and microtubule morphology. Our results demonstrate that Arabidopsis APC/C is required for meiotic chromosome segregation and that APC/C-mediated regulation of meiotic chromosome segregation is a conserved mechanism among eukaryotes.

Silencing of lncRNA LINC00514 inhibits the malignant behaviors of papillary thyroid cancer through miR-204-3p/CDC23 axis.

Numerous studies have provided that long noncoding RNAs (lncRNAs) possess important roles in regulating tumorigenesis. However, up to data, the role of LINC00514 in cancer, including thyroid cancer, remains unknown. In the present study, we found that LINC00514 expression was significantly upregulated in papillary thyroid cancer (PTC) tissues by bioinformatics analysis. Loss-of-function studies revealed that LINC00514 silencing inhibited the proliferation, migration and invasion of PTC cells while promoting apoptosis in vitro. Moreover, LINC00514 knockdown suppressed PTC growth in vivo. RNA-FISH showed that LINC00514 mainly locates in the nucleus of PTC cells. Through bioinformatics prediction, we identified that LINC00514 served as the sponge for miR-204-3p, and miR-204-3p directly targeted CDC23. Thus, LINC00514 promoted CDC23 expression via restraining miR-204-3p activity, leading to PTC progression. In sum, our findings demonstrated that LINC00514 contributes to PTC progression and might be a potential target for PTC therapy.

Hydrogen peroxide prolongs mitotic arrest in a dose dependent manner and independently of the spindle assembly checkpoint activity in Saccharomyces cerevisiae.

Oxidative stress and chromosome missegregation are important factors that are linked to aneuploidy. A major reason for chromosome missegragation is the inappropriate activity of the spindle assembly checkpoint (SAC), a conserved surveillance mechanism that monitors the state of kinetochore-microtubule attachments to ensure equal chromosome segregation in mitosis. SAC-activation induces a prolonged mitotic arrest. Mitosis is considered the most vulnerable cell cycle phase to several external signals, therefore increasing the time cells spent in this phase via mitotic arrest induction by SAC-activating agents is favorable for cancer therapy. Cancer cells also display elevated oxidative stress due to abnormally high production of reactive oxygen species (ROS). However, the effect of increased oxidative stress on the duration of mitotic arrest remains largely unknown. In this study, we investigated the effect of H2O2-induced oxidative stress on the mitotic arrest induced by a SAC-activating agent (nocodazole) in Saccharomyces cerevisiae. Our data suggest that oxidative stress prolongs SAC-activation induced mitotic arrest in a dose dependent manner. We, in addition, investigated the effect of H2O2 treatment on the mitotic arrest induced independently of SAC-activation by using a conditional mutant (cdc23) and showed that the effect of H2O2-induced oxidative stress on mitotic arrest is independent of the SAC activity.

Atomic structure of the APC/C and its mechanism of protein ubiquitination.

The anaphase-promoting complex (APC/C) is a multimeric RING E3 ubiquitin ligase that controls chromosome segregation and mitotic exit. Its regulation by coactivator subunits, phosphorylation, the mitotic checkpoint complex and interphase early mitotic inhibitor 1 (Emi1) ensures the correct order and timing of distinct cell-cycle transitions. Here we use cryo-electron microscopy to determine atomic structures of APC/C-coactivator complexes with either Emi1 or a UbcH10-ubiquitin conjugate. These structures define the architecture of all APC/C subunits, the position of the catalytic module and explain how Emi1 mediates inhibition of the two E2s UbcH10 and Ube2S. Definition of Cdh1 interactions with the APC/C indicates how they are antagonized by Cdh1 phosphorylation. The structure of the APC/C with UbcH10-ubiquitin reveals insights into the initiating ubiquitination reaction. Our results provide a quantitative framework for the design of future experiments to investigate APC/C functions in vivo.

Expression of miR-34c induces G2/M cell cycle arrest in breast cancer cells.

BACKGROUND: MicroRNA-34 is a family of three miRNAs that have been reported to function as tumor suppressor miRNAs and show decreased expression in various cancers. Here, we examine functions of miR-34c in basal-like breast cancer cells. METHODS: Data from The Cancer Genome Atlas (TCGA) were used for evaluation of expression in primary breast cancers. Cellular processes affected by miR-34c were investigated by thymidine incorporation, Annexin V-assays and cell cycle analysis using breast cancer cell lines. Effects on potential targets were analyzed with qPCR and Western blot. RESULTS: TCGA data revealed that miR-34c was expressed at lower levels in basal-like breast cancer tumors and low expression was associated with poor prognosis. Ectopic expression of miR-34c in basal-like breast cancer cell lines resulted in suppressed proliferation and increased cell death. Additionally, miR-34c influenced the cell cycle mainly by inducing an arrest in the G2/M phase. We found that expression levels of the known cell cycle-regulating miR-34 targets CCND1, CDK4 and CDK6, were downregulated upon miR-34c expression in breast cancer cell lines. In addition, the levels of CDC23, an important mediator in mitotic progression, were suppressed following miR-34c expression, and siRNAs targeting CDC23 mimicked the effect of miR-34c on G2/M arrest. However, protein levels of PRKCA, a predicted miR-34c target and a known regulator of breast cancer cell proliferation were not influenced by miR-34c. CONCLUSIONS: Together, our results support the role of miR-34c as a tumor suppressor miRNA also in breast cancer.

Mechanisms controlling the temporal degradation of Nek2A and Kif18A by the APC/C-Cdc20 complex.

The Anaphase Promoting Complex/Cyclosome (APC/C) in complex with its co-activator Cdc20 is responsible for targeting proteins for ubiquitin-mediated degradation during mitosis. The activity of APC/C-Cdc20 is inhibited during prometaphase by the Spindle Assembly Checkpoint (SAC) yet certain substrates escape this inhibition. Nek2A degradation during prometaphase depends on direct binding of Nek2A to the APC/C via a C-terminal MR dipeptide but whether this motif alone is sufficient is not clear. Here, we identify Kif18A as a novel APC/C-Cdc20 substrate and show that Kif18A degradation depends on a C-terminal LR motif. However in contrast to Nek2A, Kif18A is not degraded until anaphase showing that additional mechanisms contribute to Nek2A degradation. We find that dimerization via the leucine zipper, in combination with the MR motif, is required for stable Nek2A binding to and ubiquitination by the APC/C. Nek2A and the mitotic checkpoint complex (MCC) have an overlap in APC/C subunit requirements for binding and we propose that Nek2A binds with high affinity to apo-APC/C and is degraded by the pool of Cdc20 that avoids inhibition by the SAC.

OLSVis: an animated, interactive visual browser for bio-ontologies.

BACKGROUND: More than one million terms from biomedical ontologies and controlled vocabularies are available through the Ontology Lookup Service (OLS). Although OLS provides ample possibility for querying and browsing terms, the visualization of parts of the ontology graphs is rather limited and inflexible. RESULTS: We created the OLSVis web application, a visualiser for browsing all ontologies available in the OLS database. OLSVis shows customisable subgraphs of the OLS ontologies. Subgraphs are animated via a real-time force-based layout algorithm which is fully interactive: each time the user makes a change, e.g. browsing to a new term, hiding, adding, or dragging terms, the algorithm performs smooth and only essential reorganisations of the graph. This assures an optimal viewing experience, because subsequent screen layouts are not grossly altered, and users can easily navigate through the graph. URL: http://ols.wordvis.com CONCLUSIONS: The OLSVis web application provides a user-friendly tool to visualise ontologies from the OLS repository. It broadens the possibilities to investigate and select ontology subgraphs through a smooth visualisation method.

CDC23 regulates cancer cell phenotype and is overexpressed in papillary thyroid cancer.

Cancer gender disparities have been observed for a variety of human malignancies. Thyroid cancer is one such example where there is a dramatic difference in the incidence, aggressiveness, and death rate by gender. The molecular basis for gender disparity is poorly understood. To address this, we performed genome-wide gene expression profiling in matched papillary thyroid cancer (PTC) samples and identified nine candidate genes differentially expressed by gender. One of these genes was CDC23 that was upregulated in PTC in men compared with women. Because the function and expression of CDC23 is unknown in eukaryotic cells, we further characterized the expression of CDC23 in normal, hyperplastic, and PTC tissue samples. We found CDC23 was overexpressed in PTC and absent in normal and hyperplastic thyroid tissue. In thyroid cancer cells, functional knockdown of CDC23 resulted in an increase in the number of cells in both the S and G(2)M phases of the cell cycle, and an inhibition of cellular proliferation, tumor spheroid formation, and anchorage-independent growth. Cellular arrest in both S and G(2)M phases was associated with significant cyclin B1 and securin protein accumulation after CDC23 knockdown. Moreover, the effect of CDC23 on cellular proliferation and cell cycle progression was reversed on triple knockdown studies of CDC23, cyclin B1, and securin. Our data taken together suggests CDC23 has important biologic effects on cell proliferation and cell cycle progression. The effect of CDC23 on cellular proliferation and cell cycle progression is mediated, at least in part, by cyclin B1 and securin protein levels. Therefore, we propose that CDC23 is a critical regulator of cell cycle and cell growth, and may be involved in thyroid cancer initiation and progression, and may explain the different tumor biology observed by gender.

Structural basis for the subunit assembly of the anaphase-promoting complex.

The anaphase-promoting complex or cyclosome (APC/C) is an unusually large E3 ubiquitin ligase responsible for regulating defined cell cycle transitions. Information on how its 13 constituent proteins are assembled, and how they interact with co-activators, substrates and regulatory proteins is limited. Here, we describe a recombinant expression system that allows the reconstitution of holo APC/C and its sub-complexes that, when combined with electron microscopy, mass spectrometry and docking of crystallographic and homology-derived coordinates, provides a precise definition of the organization and structure of all essential APC/C subunits, resulting in a pseudo-atomic model for 70% of the APC/C. A lattice-like appearance of the APC/C is generated by multiple repeat motifs of most APC/C subunits. Three conserved tetratricopeptide repeat (TPR) subunits (Cdc16, Cdc23 and Cdc27) share related superhelical homo-dimeric architectures that assemble to generate a quasi-symmetrical structure. Our structure explains how this TPR sub-complex, together with additional scaffolding subunits (Apc1, Apc4 and Apc5), coordinate the juxtaposition of the catalytic and substrate recognition module (Apc2, Apc11 and Apc10 (also known as Doc1)), and TPR-phosphorylation sites, relative to co-activator, regulatory proteins and substrates.

Molecular structure of the N-terminal domain of the APC/C subunit Cdc27 reveals a homo-dimeric tetratricopeptide repeat architecture.

The anaphase promoting complex/cyclosome (APC/C) is a large multi-subunit E3 ubiquitin ligase that targets specific cell cycle regulatory proteins for ubiquitin-dependent degradation, thereby controlling cell cycle events such as the metaphase to anaphase transition and the exit from mitosis. Biochemical and genetic studies are consistent with the notion that subunits of APC/C are organised into two distinct sub-complexes; a catalytic sub-complex including the cullin domain and RING finger subunits Apc2 and Apc11, respectively, and a tetratricopeptide repeat (TPR) sub-complex composed of the TPR subunits Cdc16, Cdc23 and Cdc27 (Apc3). Here, we describe the crystal structure of the N-terminal domain of Encephalitozoon cuniculi Cdc27 (Cdc27(Nterm)), revealing a homo-dimeric structure, composed predominantly of successive TPR motifs. Mutation of the Cdc27(Nterm) dimer interface destabilises the protein, disrupts dimerisation in solution, and abolishes the capacity of E. cuniculi Cdc27 to complement Saccharomyces cerevisiae Cdc27 in vivo. These results establish the existence of functional APC/C genes in E. cuniculi, the evolutionarily conserved dimeric properties of Cdc27, and provide a framework for understanding the architecture of full-length Cdc27.

Analysis of activator-binding sites on the APC/C supports a cooperative substrate-binding mechanism.

The anaphase-promoting complex or cyclosome (APC/C) is a ubiquitin ligase essential for the completion of mitosis in all eukaryotic cells. Substrates are recruited to the APC/C by activator proteins (Cdc20 or Cdh1), but it is not known where substrates are bound during catalysis. We explored this problem by analyzing mutations in the tetratricopeptide-repeat-containing APC/C subunits. We identified residues in Cdc23 and Cdc27 that are required for APC/C binding to Cdc20 and Cdh1 and for APC/C function in vivo. Mutation of these sites increased the rate of activator dissociation from the APC/C but did not affect reaction processivity, suggesting that the mutations have little effect on substrate dissociation from the active site. Further studies revealed that activator dissociation from the APC/C is inhibited by substrate, and that substrates are not bound solely to activator during catalysis but interact bivalently with an additional binding site on the APC/C core.

An architectural map of the anaphase-promoting complex.

The anaphase-promoting complex or cyclosome (APC) is an unusually complicated ubiquitin ligase, composed of 13 core subunits and either of two loosely associated regulatory subunits, Cdc20 and Cdh1. We analyzed the architecture of the APC using a recently constructed budding yeast strain that is viable in the absence of normally essential APC subunits. We found that the largest subunit, Apc1, serves as a scaffold that associates independently with two separable subcomplexes, one that contains Apc2 (Cullin), Apc11 (RING), and Doc1/Apc10, and another that contains the three TPR subunits (Cdc27, Cdc16, and Cdc23). We found that the three TPR subunits display a sequential binding dependency, with Cdc27 the most peripheral, Cdc23 the most internal, and Cdc16 between. Apc4, Apc5, Cdc23, and Apc1 associate interdependently, such that loss of any one subunit greatly reduces binding between the remaining three. Intriguingly, the cullin and TPR subunits both contribute to the binding of Cdh1 to the APC. Enzymatic assays performed with APC purified from strains lacking each of the essential subunits revealed that only cdc27Delta complexes retain detectable activity in the presence of Cdh1. This residual activity depends on the C-box domain of Cdh1, but not on the C-terminal IR domain, suggesting that the C-box mediates a productive interaction with an APC subunit other than Cdc27. We have also found that the IR domain of Cdc20 is dispensable for viability, suggesting that Cdc20 can activate the APC through another domain. We have provided an updated model for the subunit architecture of the APC.

Depletion of anaphase-promoting complex or cyclosome (APC/C) subunit homolog APC1 or CDC27 of Trypanosoma brucei arrests the procyclic form in metaphase but the bloodstream form in anaphase.

The anaphase-promoting complex or cyclosome (APC/C) is a multiprotein subunit E3 ubiquitin ligase complex that controls segregation of chromosomes and exit from mitosis in eukaryotes. It triggers elimination of key cell cycle regulators such as securin and mitotic cyclins during mitosis by polyubiquitinating them for proteasome degradation. Seven core subunit homologs of APC/C (APC1, APC2, APC11, CDC16, CDC23, CDC27, and DOC1) were identified in the Trypanosoma brucei genome data base. Expression of six of them was individually ablated by RNA interference in both the procyclic and bloodstream forms of T. brucei. Only the CDC27- and APC1-depleted cells were enriched in the G2/M phase with inhibited growth. Further studies indicated that T. brucei APC1 and CDC27 failed to complement the corresponding deletion mutants of budding yeast. However, their depletion from procyclic-form T. brucei enriched cells with two kinetoplasts and an enlarged nucleus possessing short metaphase-like mitotic spindles, suggesting that APC1 and CDC27 may play essential roles in promoting anaphase in the procyclic form. Their depletion from the bloodstream form, however, enriched cells with two kinetoplasts and two nuclei connected through a microtubule bundle, suggesting a late anaphase arrest. This is the first time functional APC/C subunit homologs were identified in T. brucei. The apparent differential activities of this putative APC/C in two distinct developmental stages suggest an unusual function. The apparent lack of functional involvement of some of the other individual structural subunit homologs of APC/C may indicate the structural uniqueness of T. brucei APC/C.

Nuclear distribution and chromatin association of DNA polymerase alpha-primase is affected by TEV protease cleavage of Cdc23 (Mcm10) in fission yeast.

BACKGROUND: Cdc23/Mcm10 is required for the initiation and elongation steps of DNA replication but its biochemical function is unclear. Here, we probe its function using a novel approach in fission yeast, involving Cdc23 cleavage by the TEV protease. RESULTS: Insertion of a TEV protease cleavage site into Cdc23 allows in vivo removal of the C-terminal 170 aa of the protein by TEV protease induction, resulting in an S phase arrest. This C-terminal fragment of Cdc23 is not retained in the nucleus after cleavage, showing that it lacks a nuclear localization signal and ability to bind to chromatin. Using an in situ chromatin binding procedure we have determined how the S phase chromatin association of DNA polymerase alpha-primase and the GINS (Sld5-Psf1-Psf2-Psf3) complex is affected by Cdc23 inactivation. The chromatin binding and sub-nuclear distribution of DNA primase catalytic subunit (Spp1) is affected by Cdc23 cleavage and also by inactivation of Cdc23 using a degron allele, implying that DNA polymerase alpha-primase function is dependent on Cdc23. In contrast to the effect on Spp1, the chromatin association of the Psf2 subunit of the GINS complex is not affected by Cdc23 inactivation. CONCLUSION: An important function of Cdc23 in the elongation step of DNA replication may be to assist in the docking of DNA polymerase alpha-primase to chromatin.

Changes in the localization of the Saccharomyces cerevisiae anaphase-promoting complex upon microtubule depolymerization and spindle checkpoint activation.

The anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase in the ubiquitin-mediated proteolysis pathway (UMP). To understand how the APC/C was targeted to its substrates, we performed a detailed analysis of one of the APC/C components, Cdc23p. In live cells, Cdc23-GFP localized to punctate nuclear spots surrounded by homogenous nuclear signal throughout the cell cycle. These punctate spots colocalized with two outer kinetochore proteins, Slk19p and Okp1p, but not with the spindle pole body protein, Spc42p. In late anaphase, the Cdc23-GFP was also visualized along the length of the mitotic spindle. We hypothesized that spindle checkpoint activation may affect the APC/C nuclear spot localization. Localization of Cdc23-GFP was disrupted upon nocodazole treatment in the kinetochore mutant okp1-5 and in the cdc20-1 mutant. Cdc23-GFP nuclear spot localization was not affected in the ndc10-1 mutant, which is defective in spindle checkpoint function. Additional studies using a mad2Delta strain revealed a microtubule dependency of Cdc23-GFP spot localization, whether or not the checkpoint response was activated. On the basis of these data, we conclude that Cdc23p localization was dependent on microtubules and was affected by specific types of kinetochore disruption.

Fission yeast Cdc23/Mcm10 functions after pre-replicative complex formation to promote Cdc45 chromatin binding.

Using a cytological assay to monitor the successive chromatin association of replication proteins leading to replication initiation, we have investigated the function of fission yeast Cdc23/Mcm10 in DNA replication. Inactivation of Cdc23 before replication initiation using tight degron mutations has no effect on Mcm2 chromatin association, and thus pre-replicative complex (pre-RC) formation, although Cdc45 chromatin binding is blocked. Inactivating Cdc23 during an S phase block after Cdc45 has bound causes a small reduction in Cdc45 chromatin binding, and replication does not terminate in the absence of Mcm10 function. These observations show that Cdc23/Mcm10 function is conserved between fission yeast and Xenopus, where in vitro analysis has indicated a similar requirement for Cdc45 binding, but apparently not compared with Saccharomyces cerevisiae, where Mcm10 is needed for Mcm2 chromatin binding. However, unlike the situation in Xenopus, where Mcm10 chromatin binding is dependent on Mcm2-7, we show that the fission yeast protein is bound to chromatin throughout the cell cycle in growing cells, and only displaced from chromatin during quiescence. On return to growth, Cdc23 chromatin binding is rapidly reestablished independently from pre-RC formation, suggesting that chromatin association of Cdc23 provides a link between proliferation and competence to execute DNA replication.

Human T-lymphotropic virus type 1 oncoprotein tax promotes unscheduled degradation of Pds1p/securin and Clb2p/cyclin B1 and causes chromosomal instability.

Human T-lymphotropic virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia. The HTLV-1 transactivator, Tax, is implicated as the viral oncoprotein. Naïve cells expressing Tax for the first time develop severe cell cycle abnormalities that include increased DNA synthesis, mitotic arrest, appearance of convoluted nuclei with decondensed DNA, and formation of multinucleated cells. Here we report that Tax causes a drastic reduction in Pds1p/securin and Clb2p/cyclin B levels in yeast, rodent, and human cells and a loss of cell viability. With a temperature-sensitive mutant of the CDC23 subunit of the anaphase-promoting complex (APC), cdc23(ts); a temperature-sensitive mutant of cdc20; and a cdh1-null mutant, we show that the diminution of Pds1p and Clb2p brought on by Tax is mediated via the Cdc20p-associated anaphase-promoting complex, APC(Cdc20p). This loss of Pds1p/securin and Clb2p/cyclin B1 occurred before cellular entry into mitosis, caused a G(2)/M cell cycle block, and was accompanied by severe chromosome aneuploidy in both Saccharomyces cerevisiae cells and human diploid fibroblasts. Our results support the notion that Tax aberrantly targets and activates APC(Cdc20p), leading to unscheduled degradation of Pds1p/securin and Clb2p/cyclin B1, a delay or failure in mitotic entry and progression, and faulty chromosome transmission. The chromosomal instability resulting from a Tax-induced deficiency in securin and cyclin B1 provides an explanation for the highly aneuploid nature of adult T-cell leukemia cells.