Cdc14

Biochemical switches in the cell cycle

Mitotic exit

PRC1

Mitosis

SKA2

Securin

Cohesin

Spindle checkpoint

Frank Uhlmann

Cytokinesis

Cyclin A2

Spindle apparatus

DCTN6

USP16

Polo-like kinase

BUB3

ZW10

MAD2L1BP

MAD2L1

MAD2L2

MAD1L1

Separase

CDC27

CDC16

Mad1

KIF2C

Maturation promoting factor

BUB1B

Biorientation

Proteasome

RNA interference

Apoptosis

Cell cycle checkpoint

Centrosome cycle

RNA interference

Geminin

Clb 5,6 (Cdk1)

Kinesin family member 11

Cell division control protein 4

Proteasome

Securin1

• Separase is a protease whose liberation from its inhibitory chaperone Securin triggers sister chromatid disjunction at anaphase onset in yeast by cleaving cohesin's kleisin subunit. (ox.ac.uk)

Metaphase-to-anaphase9

• The metaphase-to-anaphase I transition is a key step in the completion of meiosis I. In mouse oocytes, competence to exit metaphase I (MI) is developmentally regulated and typically not acquired until the preovulatory stage. (bioone.org)
• In the first APC-mediated cell-cycle transition, degradation of the anaphase-inhibitor protein securin, called Pds1p in S. cerevisiae , elicits sister chromatid separation and, thereby, initiates the metaphase-to-anaphase transition ( 21 , 22 ). (pnas.org)
• Unequal inheritance of chromosomes (aneuploidy) is a cause of a number of disorders, particularly in humans, even though eukaryotic cells can arrest or delay the transition from metaphase to anaphase if an event critical to the completion of metaphase is impaired. (springer.com)
• Thus, catenations must be resolved by DNA topoisomerase II at the metaphase-to-anaphase transition to allow segregation of sisters. (umn.edu)
• When multinucleates were treated with ICRF-193 at the metaphase-to-anaphase transition, tangled and untangled anaphases were observed within the same cell. (umn.edu)
• We have isolated mad2 , a spindle checkpoint component in fission yeast, and shown that mad2 overexpression activates the checkpoint and causes a cell cycle arrest at the metaphase-to-anaphase transition. (pnas.org)
• Eukaryotic cells have solved this 'anaphase problem' by disabling the mitotic checkpoint at the metaphase-to-anaphase transition. (biochemsoctrans.org)
• CDC27 is a core component of the anaphase-promoting complex/cyclosome (APC/C), a multisubunit E3 ubiquitin ligase, whose oscillatory activity is responsible for the metaphase-to-anaphase transition and mitotic exit. (aacrjournals.org)
• The anaphase-promoting complex/cyclosome (APC/C) is a major E3 ligase complex that promotes the metaphase-to-anaphase transition, and its activation is inhibited until surveillance mechanisms within the cell sense proper metaphase alignment and bipolar spindle attachment of chromosomes ( 2, 3 ). (aacrjournals.org)

Cyclosome18

• One mechanism that controls mitotic transitions is regulated proteolysis mediated by a multisubunit ubiquitin-protein ligase known as the anaphase-promoting complex (APC) or cyclosome ( 18 ). (pnas.org)
• The only element in this ubiquitination pathway whose activity is cell-cycle regulated is the ubiquitin ligase (E3), also called the cyclosome or anaphase promoting complex (APC) ( 15 - 17 ). (pnas.org)
• The cell cycle is regulated by the S phase kinase-associated protein 1 (SKP1)-cullin 1 (CUL1)-F-box protein (SCF) and anaphase-promoting complex/cyclosome (APC/C) multisubunit RING finger E3s. (nature.com)
• Many RING finger E3s have roles in processes that are central to the maintenance of genomic integrity and cellular homeostasis, such as the anaphase promoting complex/cyclosome (APC/C), the SKP1-cullin 1-F-box protein (SCF) E3s, MDM2, BRCA1, Fanconi anaemia proteins, CBL proteins, von Hippel-Lindau tumour suppressor (VHL) and SIAH proteins. (nature.com)
• One of the key regulators of the SAC is the anaphase promoting complex/cyclosome (APC/C) which ubiquitinates cyclin B and securin and targets them for proteolysis. (biomedcentral.com)
• APC16 is a conserved subunit of the anaphase-promoting complex/cyclosome. (harvard.edu)
• The anaphase promoting complex or cyclosome is the ubiquitin-ligase that targets destruction box-containing proteins for proteolysis during the cell cycle. (plantphysiol.org)
• Anaphase promoting complex or cyclosome and its activator (the fizzy and fizzy-related) proteins work together with ubiquitin-conjugating enzymes (UBCs) (E2s). (plantphysiol.org)
• The anaphase-promoting complex/cyclosome (APC/C) promotes anaphase onset and mitotic exit through ubiquitinating securin and cyclin B1. (rcsb.org)
• Aurora-B binding partners switched dramatically between M phase to C phase, and we identified several novel C phase-selective Aurora-B binding partners including PRC1, KIF4, and anaphase-promoting complex/cyclosome. (mcponline.org)
• This method works in part by global inhibition of CDK1, in part by activation of phosphatases ( 5 ), and in part by activating Cdh1 (through loss of inhibitory CDK1 phosphorylation ( 10 )), which activates the anaphase-promoting complex/cyclosome (APC/C). 1 The net effect is to mimic most or all of the known regulation that occurs after normal anaphase onset. (mcponline.org)
• As a result, stable attachment of the final chromosome satisfies the SAC, permitting activation of the anaphase promoting complex/cyclosome (APC/C) and subsequent anaphase onset. (springer.com)
• MAD1-MAD2 catalyzes production of an inhibitor of the anaphase-promoting complex/cyclosome (APC/C), resulting in maintenance of sister chromatid cohesion and of the mitotic state (De Antoni et al. (springer.com)
• The anaphase-promoting complex/cyclosome (APC/C) is a multisubunit ubiquitin ligase that regulates progression through the cell cycle by marking key cell division proteins for destruction. (meta.org)
• The anaphase‐promoting complex (APC) or cyclosome is a ubiquitin ligase that initiates anaphase and mitotic exit. (embopress.org)
• Likewise, Cdc20, an activator of the anaphase-promoting complex/cyclosome, is excluded from interphase nuclei, but enters nuclei at mitotic onset and accumulates to a higher level in mitotic nuclei than in the surrounding nucleoplasm before leaving in anaphase/telophase. (embl-heidelberg.de)
• Here we report that inhibition of MPS1 kinase activity by reversine disrupts BUBR1-MAD2 as well as CDC20-MAD2 interactions, causing premature activation of the anaphase-promoting complex/cyclosome. (embl-heidelberg.de)
• In biochemical terms, the SAC acts by inhibiting the Cdc20-bound form of the anaphase-promoting complex/cyclosome (APC/C), a large ubiquitin protein ligase ( Peters, 2006 ). (pubmedcentralcanada.ca)

Ubiquitin-protei1

• Degradation required the ubiquitin protein ligase called the anaphase-promoting complex, the anaphase-promoting complex activating protein Cdc20, and a unique 43-aa sequence in Kip1p. (pnas.org)

Separase4

• Cleaved by separase/ESPL1 at the onset of anaphase. (abcam.com)
• The shugoshin (Sgo1)-PP2A complex protects centromeric cohesin until its cleavage by separase at anaphase onset. (rcsb.org)
• At the beginning of anaphase the enzymes separase cleaves choesin and the centromeres slit. (studystack.com)
• Destruction of the inhibitory protein securin releases active separase, which triggers sister chromatid separation and anaphase onset by cleaving cohesin. (plantcell.org)

Cytokinesis5

• Therefore, cells with an anaphase spindle that is inappropriately positioned within the mother cell would cause cytokinesis to occur parallel to the plane of the spindle and, thus, result in aneuploidy. (rupress.org)
• Chromosome tips damaged in anaphase inhibit cytokinesis. (harvard.edu)
• Aurora B phosphorylates MKlp1 during anaphase and is required for its function in cytokinesis. (nih.gov)
• This may be explained by a process initiated by telomeric dysfunction and anaphase bridging, which may give rise to an increased frequency of multinucleated cells because of cytokinesis failure ( 3 ). (aacrjournals.org)
• Anaphase A chromosome movement appears to be normal, however cytokinesis often fails. (sdbonline.org)

Kinetochore2

• A kinetochore-independent mechanism drives anaphase chromosome separation during acentrosomal meiosis. (nih.gov)
• We previously described a physical reorganization that takes place within the kinetochore, called intrakinetochore stretch, that correlates with kinetochore phosphorylation and generation of the "wait-anaphase" signal (Maresca & Salmon, JCB, 2009). (umass.edu)

Elongation9

• Cortical dynein and asymmetric membrane elongation coordinately position the spindle in anaphase. (nih.gov)
• We examined spindle elongation in anaphase in Saccharomyces cerevisiae cells mutated for the kinesin-5 motor proteins Cin8 and Kip1. (biologists.org)
• We found that, in kinesin-5-mutated cells, predominantly in kip1 Δ cin8-F467A cells, anaphase spindle elongation was frequently interrupted after the fast phase, resulting in a mid-anaphase pause. (biologists.org)
• We also examined the effects of components of the FEAR pathway, which is involved in the early-anaphase activation of Cdc14 regulatory phosphatase, on anaphase spindle elongation in kip1 Δ cin8-F467A cells. (biologists.org)
• Anaphase-B spindle elongation is the final phase of bipolar spindle morphogenesis, during which the spindle elongates dramatically, as much as two to five times its pre-anaphase length, thus spatially separating sister chromatids. (biologists.org)
• However, the mechanisms by which kinesin-5 motor proteins perform their anaphase spindle-elongation functions are not well understood. (biologists.org)
• In S. cerevisiae cells, anaphase-B spindle elongation proceeds in two phases. (biologists.org)
• In addition, anaphase cells show the presence of lagging chromosomes and a defect in spindle elongation. (genetics.org)
• We further reveal how the velocity of spindle elongation is regulated: coupled to cell size, the amount of kinesin-6 Klp9 molecules increases, resulting in an acceleration of spindle elongation in anaphase B. In addition, the number of Klp9 binding sites to microtubules increases overproportionally to Klp9 molecules, suggesting that molecular crowding inversely correlates to cell size and might have an impact on spindle elongation velocity control. (elifesciences.org)

Microtubules1

• During anaphase, microtubules then form between the separating chromosomes. (nih.gov)

Segregation4

• In this report, we review recent advances in our knowledge of how the complex process of chromosome segregation is coupled with cell cycle progression, and starts at onset of anaphase with sister chromatids separation of the replicated chromosomes. (springer.com)
• In eukaryotic cells, the strategy to ensure physical segregation of chromosomes to daughter cells relies on two basic steps ordered in time: an initial linkage, or cohesion, of sister chromatids and its timely and complete dissolution during anaphase. (imperial.ac.uk)
• In anaphase, rDNA becomes repressed allowing for local condensation and segregation before the next cell cycle initiates. (ieo.it)
• We show that the interaction of EB1 with Astrin-SKAP complex, a key regulator of chromosome segregation, is enhanced during prometaphase, compared to anaphase. (elsevier.com)

Separation5

• The loss of KIP1 and CIN8 function after spindle assembly but before anaphase results in the collapse of the spindle, indicating a role in the maintenance of pole separation ( 10 ). (pnas.org)
• After anaphase initiation, the loss of function results in slowed anaphase progression, suggesting that these kinesins play a nonessential role in pole separation during anaphase ( 16 , 17 ). (pnas.org)
• The separation of chromosomes in anaphase is a precarious step in the cell cycle. (stanford.edu)
• Separation of the sister chromatids during anaphase II pulls a haploid set of chromosomes into each of four lobes of the nucleus. (asm.org)
• The brk1 mutants are sterile due to the precocious separation of sister chromatids at the onset of anaphase I. The centromeric recruitment of SHUGOSHIN1 and phosphorylation of histone H2A at Thr-134 (H2A-pT134) depend on BRK1. (plantcell.org)

Protein2

• The GTP-bound form of Spg1p recruits the Cdc7p protein kinase, resulting in Cdc7p localization to both SPBs during metaphase and just one SPB during anaphase B ( 33 ). (asm.org)
• CYCA2;3 protein stability was found to be controlled by CCS52A1, an activator of the anaphase-promoting complex. (ugent.be)

Delays the onset of anaphase1

• Eukaryotic cells have evolved a mechanism that delays the onset of anaphase until condensed chromosomes are properly positioned on the mitotic spindle. (aacrjournals.org)

Cohesin3

• In cul-2 mutants, the cohesin REC-8 is removed from chromosomes normally during meiosis II and sister chromatids separate, suggesting that the failure to complete anaphase results from a defect in chromosome movement rather than from a failure to sever chromosome attachments. (biologists.org)
• This analysis revealed Sgo1, Chl4, and Iml3 to be important for retaining centromeric cohesin until the onset of anaphase II. (sciencemag.org)
• Cohesin holds sister chromatids together prior to their proper attachment to spindles and alignment on the metaphase plate preceding anaphase ( Nasmyth and Haering 2009 ). (g3journal.org)

Inhibits1

• Treatment of late metaphase cells with 1 μM taxol inhibits anaphase onset, but produces the same kMt distribution as in early anaphase: 28.7 ± 7.4 ( n = 54). (rupress.org)

Progression3

• In both systems, transient suppression of endogenous PKC activity by treatment with a PKC-specific inhibitor, bisindolylmaleimide I (BIM), promoted the onset of anaphase I in a dose-dependent manner, while activation of PKC with the phorbol ester TPA blocked progression to MII. (bioone.org)
• A mutation that stabilized Kip1p impaired anaphase progression. (pnas.org)
• Dephosphorylation by PPP2CA leads to enhancement of NuMA at the cell cortex in anaphase and proper cell-cycle progression (5,6). (cellsignal.com)

Degradation2

• Here, we show that Kip1p is regulated immediately after anaphase initiation by its rapid degradation. (pnas.org)
• The timing of degradation suggests that Kip1p functions primarily during spindle assembly and metaphase, and that Kip1p degradation facilitates structural changes in the mitotic spindle as anaphase progresses. (pnas.org)

Mechanism2

• A passive mechanism could maintain catenations holding sisters until the onset of anaphase. (umn.edu)
• A timing mechanism (a common trigger for two processes taking different times to be completed) could passively couple the resolution of the last remaining catenations to the moment of anaphase onset. (umn.edu)

Telophase2

• The immunostaining of the centrosomes by the anti-Polo antibody is progressively lost during anaphase-telophase concurrently with an increase in the staining of the midbody. (sdbonline.org)
• In Drosophila melanogaster embryonic epithelial cells, constriction occurs during anaphase B and telophase to generate two daughter cells, each containing one set of the recently separated sister chromatids. (sdbonline.org)

Early anaphase release1

• a process that is governed by the FEAR (Cdc fourteen early anaphase release) pathway. (biologists.org)

Promotes anaphase1

• These findings suggest that Cdc20p is a limiting factor that promotes anaphase entry by antagonizing Pds1p. (genetics.org)

Centromeres3

• The centromeres separate at the onset of anaphase. (coursehero.com)
• Another kinesin-6 family motor, MKlp2, mediates the relocation of Aurora B from the centromeres to the central spindle at the onset of anaphase. (nih.gov)
• DmAurora B is required for DmINCENP accumulation at centromeres and transfer to the spindle at anaphase. (sdbonline.org)

Inactivation1

• We show that inactivation of CUL-2, a member of the cullin family of ubiquitin ligases, delays or abolishes meiotic anaphase II with no effect on anaphase I, indicating differential regulation during the two meiotic stages. (biologists.org)

Meiotic2

• Currently, little is known about the molecular mechanisms regulating the initiation and completion of meiotic anaphase. (biologists.org)
• In contrast to the detailed information about chromosome cohesion and its dissolution, little is known about the mechanisms that regulate chromosome movement during meiotic anaphase. (biologists.org)

Epithelial cells1

• orientation, and anaphase onset in epithelial cells. (xenbase.org)

Spindles2

• Kip1p and Cin8p localization have been detected on unassembled spindles and on preanaphase spindles, but not on anaphase spindles ( 8 , 9 ). (pnas.org)
• We found that sea urchin zygotes containing tripolar or tetrapolar spindles progressed from nuclear envelope breakdown to anaphase onset with normal timing. (biologists.org)

Sister3

• Treatment of Allium cepa meristematic cells in metaphase with the topoisomerase II inhibitor ICRF-193, results in bridging of the sister chromatids at anaphase. (umn.edu)
• But this possibility was dismissed as acentric chromosome fragments were able to separate their sister chromatids at anaphase. (umn.edu)
• This cleavage liberates tethered sister chromatids, permitting anaphase to ensue. (asm.org)

Initiation1

• Indeed, overproduction of nondestructible Cdc13p prevents septation in APC cut mutants and the normal reorganization of septation initiation network components during anaphase. (asm.org)

Defects1

• Deletion of SLK19 , but not SPO12 , eliminated the mid-anaphase pause, caused premature anaphase onset and defects in DNA division during anaphase, and reduced viability in these cells. (biologists.org)

Subsequent2

• Therefore, the silencing of the SAC is thought to trigger anaphase onset, but how correct chromosome attachment is coupled with SAC silencing and the subsequent anaphase onset is poorly understood. (embl-heidelberg.de)
• Therefore, this signaling pathway ensures that SAC silencing and the subsequent anaphase onset occur only after chromosome bipolar attachment applies tension on chromosomes. (embl-heidelberg.de)

Cdc202

• Previous studies indicated that loss of CDC20 function caused cell cycle arrest prior to the onset of anaphase. (genetics.org)
• CDC20 overexpression was unable to promote anaphase in cells deficient in APC function. (genetics.org)

Attachment1

• Therefore, we speculate that BRK1 may be required for normal localization of Aurora kinase before the onset of metaphase I, which is responsible for correcting the merotelic attachment. (plantcell.org)