DOCSLIB.ORG

The Anaphase Promoting Complex/ Cyclosome: a Machine Designed to Destroy

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Anaphase Promoting Complex/ Cyclosome: a Machine Designed to Destroy REVIEWS The anaphase promoting complex/ cyclosome: a machine designed to destroy Jan-Michael Peters Abstract | The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex. Recent discoveries have revealed an unexpected multitude of mechanisms that control APC/C activity, and have provided a first insight into how this unusual ubiquitin ligase recognizes its substrates. Ubiquitin ligase (E3) Cell proliferation in all eukaryotes depends strictly In this article I discuss how APC/C might be able to The third enzyme in a series — on the ubiquitin ligase (E3) activity of the anaphase selectively recognize its substrates, and review recent dis- the first two are designated promoting complex/cyclosome (APC/C). APC/C is a coveries that have provided new insights into the essential ubiquitin-activating (E1) and 1.5-MDa protein complex that is found in the nucleus mitotic functions of APC/C and its regulation during ubiquitin-conjugating (E2) — of interphase cells, and that spreads throughout the the cell cycle. But first I describe the APC/C complex that is responsible for the ubiquitylation of target cytoplasm and associates with parts of the spindle and its cofactors, and their roles in APC/C-mediated proteins. E3 enzymes provide apparatus during mitosis. Without APC/C, cells cannot ubiquitylation. platforms for binding E2 separate their sister chromatids in anaphase, they enzymes and specific cannot exit from mitosis and divide into two daughter The APC/C complex and its cofactors substrates, thereby coor dina ting the cells, and they cannot initiate the steps that are nec- APC/C is composed of at least a dozen different sub- ubiquitylation of selected essary for DNA replication later in S phase. APC/C units (TABLE 1), but it can only ubiquitylate substrates substrates. seems to have similarly important functions in meiosis, with the help of three cofactors, the ubiquitin-activating and a number of observations imply that APC/C has (E1) enzyme, a ubiquitin-conjugating (E2) enzyme and a Polyubiquitin chains also adopted new roles during the evolution of multi- co-activator protein. Protein assemblies that are composed of several copies cellular organisms in postmitotic differentiated cells of the small protein ubiquitin. (reviewed in REFS 1,2). APC/C cofactors. Like all E3 enzymes, APC/C uses The ubiquitin residues are In all known cases, APC/C performs its various ubiquitin residues that have been activated by E1 and covalently attached to each functions by assembling polyubiquitin chains on then transferred to E2 enzymes. APC/C can collaborate other through isopeptide bonds. substrate proteins (Supplementary information S1 with two E2 enzymes, UBCH5 and UBCH10 (which (table)), which targets these proteins for destruction is also known as E2-C or UbcX)3,4. Although each of by the 26S proteasome. Proteolysis is inherently asso- these is sufficient to support APC/C-mediated ubiq- ciated with inactivation, which is what APC/C does uitylation reactions in vitro, UBCH10 orthologues in in a number of cases in which its substrate protein is human cells, Drosophila melanogaster and fission yeast either a catalytic protein or an essential activator of are essential for the initiation of anaphase, indicating such an enzyme. Prominent examples of these types that UBCH5 alone cannot fully support APC/C activity of APC/C substrate are the mitosis-specific Aurora in vivo5–7. A possible exception is budding yeast, in kinases and Polo-like kinase-1 (Plk1), and mitotic which Ubc5 alone seems to be sufficient for APC/C Research Institute of 8 Molecular Pathology, A- and B-type cyclins, the activating subunits of function . Dr. Bohr-Gasse 7, cyclin-dependent kinases-1 and -2 (Cdk1 and Cdk2). UBCH5 and UBCH10 associate with APC/C only A-1030 Vienna, Austria. However, APC/C can also activate proteins, in this transiently9. However, it is unknown whether the e-mail: case, by targeting inhibitors of these proteins for dynamic nature of this interaction is required for [email protected] doi:10.1038/nrm1988 destruction. Famous examples are securin, an inhibi- ubiquitylation reactions, as has been proposed to be 10 Published online tor of the protease separase, and geminin, a protein the case for the ubiquitin ligase SCF , or whether the 9 August 2006 that inactivates the replication factor CTD1. transient nature of APC/C–E2 interactions is simply a 644 | SEPTEMBER 2006 | VOLUME 7 www.nature.com/reviews/molcellbio © 2006 Nature Publishing Group REVIEWS Table 1 | APC/C subunits and co-activators Vertebrates Drosophila Budding yeast Structural motifs Functions melanogaster 26S proteasome Subunits A large multisubunit protease complex that selectively APC1/TSG24 Shattered Apc1 RPN1 and RPN2 homology* - degrades multi-ubiquitylated APC2 Morula Apc2 Cullin homology APC11 and DOC1 proteins. It contains a 20S binding particle that carries the catalytic activity and two CDC27/APC3 Makos Cdc27 TPRs CDH1 binding regulatory 19S particles. APC4 - Apc4 WD40 repeats - Cyclin-dependent kinase APC5 Ida Apc5 TPRs - (Cdk). A protein kinase that CDC16/APC6 - Cdc16 TPRs - has activity that depends on an association with a cyclin APC7 - - TPRs - subunit. Cdks are essential for CDC23/APC8 - Cdc23 TPRs - DNA replication and entry into mitosis. DOC1/APC10 - Doc1/Apc10 Doc domain Substrate recognition, processivity Ubiquitin-activating (E1) enzyme APC11 Lemming Apc11 RING-H2 finger E2 recruitment, E3 An enzyme that activates the activity C-terminal glycine residue of CDC26 - Cdc26 - - the small protein ubiquitin, allowing it to form a high- SWM1/APC13 - Swm1/Apc13 - - energy thioester bond to a --Apc9- - specific cysteine residue of the E1. E1 then transfers this - - Mnd2 - Ama1 inhibition activated form of ubiquitin Co-activators onto ubiquitin-conjugating (E2) enzymes. CDC20/p55CDC Fizzy Cdc20 C-box, WD40 repeats and IR-tail Substrate recognition CDH1 A–D Fizzy-related Cdh1/Hct1 C-box, WD40 repeats and IR-tail Substrate recognition Ubiquitin-conjugating (E2) enzyme - Rap - C-box, WD40 repeats and IR-tail Substrate recognition An enzyme that forms a - - Ama1 C-box, WD40 repeats and IR-tail Substrate recognition thioester bond with a ubiquitin residue, which is - Cortex - C-box, WD40 repeats and IR-tail Substrate recognition transferred to the E2 enzyme *RPN1 and RPN2 are subunits of the 26S proteasome. Ama1, activator of meiotic APC/C protein-1; APC/C, anaphase promoting from ubiquitin-activating (E1) complex/cyclosome; E2, ubiquitin-conjugating enzyme; E3, ubiquitin ligase; Mnd2, meiotic nuclear division protein-2; swm/SWM, enzyme. E2 uses the high spore wall maturation; TPRs, tetratrico peptide repeats; TSG, testis-specific gene. energy from the thioester bond to generate an isopeptide bond between the ubiquitin residue and a lysine reflection of the modularity of the ubiquitin system, APC/C: a cullin–RING-finger ubiquitin ligase. APC/C residue on a substrate in which a few E2 enzymes can interact with different is thought to be a distant relative of the ubiquitin ligase protein. E3 enzymes. Consistent with the possibility that the SCF because both contain subunits with cullin and RING- finger 17–19 SCF transient interaction is a reflection of the modularity of domains . In the APC/C, the cullin domain A multisubunit ubiquitin the ubiquitin system, UBCH5 is a highly promiscuous of Apc2 is associated with the RING-finger domain of ligase complex that is enzyme that can interact with several E3 enzymes, Apc11 (REFS 13,20), which in turn interacts with E2 composed of two scaffolding possibly in contrast to UBCH10, which so far is only enzymes21,22. Remarkably, Apc11 and the E2 enzyme subunits (cullin and Skp1), a known to support APC/C. UBCH5 alone can efficiently catalyse ubiquitylation RING-finger subunit that binds ubiquitin-conjugating In addition to E2 enzymes, APC/C activity is also reactions in vitro, albeit with reduced substrate spe- (E2) enzymes and one of strictly dependent on one of several co-activator cificity, indicating that other APC/C subunits are not many F-box subunits that proteins that associate with APC/C during specific absolutely essential for the E3 activity of APC/C20–22. recruit substrates. periods of the cell cycle. The best studied of these are There is no evidence that Apc11 participates directly in C-box Cdc20 and Cdh1, which are encoded by all known the transfer of ubiquitin residues onto substrates, and A sequence element eukaryotic genomes, but additional meiosis-specific it is therefore generally believed that APC/C serves as (consensus DRF/YIPXR) that APC/C co-activators have been identified in yeast a scaffold that brings E2 enzymes and substrates into was first found in the and D. melanogaster (TABLE 1). All of these proteins close proximity (reviewed in REF. 23). N-terminal region of Cdc20. are characterized by the presence of sequence ele- It remains a big mystery why APC/C is composed It is conserved in all known 11 12,13 APC/C co-activators. ments, known as the C-box and the IR-tail , that of many different subunits (12 have been identified in mediate their binding to APC/C11–13. Also, all APC/C humans and 13 in budding yeast; TABLE 1), although IR-tail co-activators contain a C-terminal WD40 domain that it takes only four proteins to build a functional SCF A sequence element is predicted to fold into a propeller-like structure, and (reviewed in REF. 24). Biochemical fractionation and (consensus IR) at the extreme C terminus of APC/C that is now believed to recognize APC/C substrates by scanning transmission electron microscopy (EM) co-activators and the APC/C interacting with specific recognition elements in these experiments indicate that APC/C from animal cells subunit Doc1.
Load more

Recommended publications
  • Mad1 Kinetochore Recruitment by Mps1-Mediated Phosphorylation of Bub1 Signals the Spindle Checkpoint
    Downloaded from genesdev.cshlp.org on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press Mad1 kinetochore recruitment by Mps1-mediated phosphorylation of Bub1 signals the spindle checkpoint Nitobe London1,2 and Sue Biggins1,3 1Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA; 2Molecular and Cellular Biology Program, University of Washington/Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA The spindle checkpoint is a conserved signaling pathway that ensures genomic integrity by preventing cell division when chromosomes are not correctly attached to the spindle. Checkpoint activation depends on the hierarchical recruitment of checkpoint proteins to generate a catalytic platform at the kinetochore. Although Mad1 kinetochore localization is the key regulatory downstream event in this cascade, its receptor and mechanism of recruitment have not been conclusively identified. Here, we demonstrate that Mad1 kinetochore association in budding yeast is mediated by phosphorylation of a region within the Bub1 checkpoint protein by the conserved protein kinase Mps1. Tethering this region of Bub1 to kinetochores bypasses the checkpoint requirement for Mps1-mediated kinetochore recruitment of upstream checkpoint proteins. The Mad1 interaction with Bub1 and kinetochores can be reconstituted in the presence of Mps1 and Mad2. Together, this work reveals a critical mechanism that determines kinetochore activation of the spindle checkpoint. [Keywords: kinetochore; spindle checkpoint; Mps1 kinase; Mad1; Bub1 kinase] Supplemental material is available for this article. Received October 25, 2013; revised version accepted December 13, 2013. Successful eukaryotic cell division requires accurate the conserved checkpoint proteins Mps1, Bub1, Bub3, chromosome segregation, which relies on correct attach- Mad1, and Mad2 as well as the Mad3 homolog BubRI in ments of spindle microtubules to chromosomes.
    [Show full text]
  • Mitosis Vs. Meiosis
    Mitosis vs. Meiosis In order for organisms to continue growing and/or replace cells that are dead or beyond repair, cells must replicate, or make identical copies of themselves. In order to do this and maintain the proper number of chromosomes, the cells of eukaryotes must undergo mitosis to divide up their DNA. The dividing of the DNA ensures that both the “old” cell (parent cell) and the “new” cells (daughter cells) have the same genetic makeup and both will be diploid, or containing the same number of chromosomes as the parent cell. For reproduction of an organism to occur, the original parent cell will undergo Meiosis to create 4 new daughter cells with a slightly different genetic makeup in order to ensure genetic diversity when fertilization occurs. The four daughter cells will be haploid, or containing half the number of chromosomes as the parent cell. The difference between the two processes is that mitosis occurs in non-reproductive cells, or somatic cells, and meiosis occurs in the cells that participate in sexual reproduction, or germ cells. The Somatic Cell Cycle (Mitosis) The somatic cell cycle consists of 3 phases: interphase, m phase, and cytokinesis. 1. Interphase: Interphase is considered the non-dividing phase of the cell cycle. It is not a part of the actual process of mitosis, but it readies the cell for mitosis. It is made up of 3 sub-phases: • G1 Phase: In G1, the cell is growing. In most organisms, the majority of the cell’s life span is spent in G1. • S Phase: In each human somatic cell, there are 23 pairs of chromosomes; one chromosome comes from the mother and one comes from the father.
    [Show full text]
  • Polo-Like Kinase 1: Target and Regulator of Anaphase-Promoting Complex/Cyclosome–Dependent Proteolysis Frank Eckerdt1 and Klaus Strebhardt2
    Review Polo-Like Kinase 1: Target and Regulator of Anaphase-Promoting Complex/Cyclosome–Dependent Proteolysis Frank Eckerdt1 and Klaus Strebhardt2 1Department of Pharmacology, University of Colorado School of Medicine, Denver, Colorado and 2Department of Gynecology and Obstetrics, Medical School, J.W. Goethe-University, Frankfurt, Germany Abstract to the regulation of the APC/C, an E3 ubiquitin ligase that is Polo-like kinase 1 (Plk1) is a key regulator of progression responsible for the timely destruction of various mitotic proteins, through mitosis. Although Plk1 seems to be dispensable for thereby regulating chromosome segregation, exit from mitosis, entry into mitosis, its role in spindle formation and exit from and a stable subsequent G1 phase (3).The APC/C is first activated by the ancillary protein Cdc20, targeting proteins containing a mitosis is crucial. Recent evidence suggests that a major role Cdc20 of Plk1 in exit from mitosis is the regulation of inhibitors of destruction box (D box), like securin.Once APC/C has the anaphase-promoting complex/cyclosome (APC/C), such as initiated mitotic exit, Cdc20 itself is degraded and is replaced by Cdh1, allowing the degradation of a wider spectrum of substrates. the early mitotic inhibitor 1 (Emi1) and spindle checkpoint Cdh1 proteins. Thus, Plk1 and the APC/C control mitotic regulators The APC/C complex targets not only D box–containing proteins but also proteins exhibiting a KEN box and/or an A box by both phosphorylation and targeted ubiquitylation to Cdh1 ensure the fidelity of chromosome separation at the meta- (e.g., cyclin B1 and Aurora A). Plk1 itself is an APC/C target.
    [Show full text]
  • 1 Spindle Assembly Checkpoint Is Sufficient for Complete Cdc20
    Spindle assembly checkpoint is sufficient for complete Cdc20 sequestering in mitotic control Bashar Ibrahim Bio System Analysis Group, Friedrich-Schiller-University Jena, and Jena Centre for Bioinformatics (JCB), 07743 Jena, Germany Email: [email protected] Abstract The spindle checkpoint assembly (SAC) ensures genome fidelity by temporarily delaying anaphase onset, until all chromosomes are properly attached to the mitotic spindle. The SAC delays mitotic progression by preventing activation of the ubiquitin ligase anaphase-promoting complex (APC/C) or cyclosome; whose activation by Cdc20 is required for sister-chromatid separation marking the transition into anaphase. The mitotic checkpoint complex (MCC), which contains Cdc20 as a subunit, binds stably to the APC/C. Compelling evidence by Izawa and Pines (Nature 2014; 10.1038/nature13911) indicates that the MCC can inhibit a second Cdc20 that has already bound and activated the APC/C. Whether or not MCC per se is sufficient to fully sequester Cdc20 and inhibit APC/C remains unclear. Here, a dynamic model for SAC regulation in which the MCC binds a second Cdc20 was constructed. This model is compared to the MCC, and the MCC-and-BubR1 (dual inhibition of APC) core model variants and subsequently validated with experimental data from the literature. By using ordinary nonlinear differential equations and spatial simulations, it is shown that the SAC works sufficiently to fully sequester Cdc20 and completely inhibit APC/C activity. This study highlights the principle that a systems biology approach is vital for molecular biology and could also be used for creating hypotheses to design future experiments. Keywords: Mathematical biology, Spindle assembly checkpoint; anaphase promoting complex, MCC, Cdc20, systems biology 1 Introduction Faithful DNA segregation, prior to cell division at mitosis, is vital for maintaining genomic integrity.
    [Show full text]
  • Kinetochores, Microtubules, and Spindle Assembly Checkpoint
    Review Joined at the hip: kinetochores, microtubules, and spindle assembly checkpoint signaling 1 1,2,3 Carlos Sacristan and Geert J.P.L. Kops 1 Molecular Cancer Research, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands 2 Center for Molecular Medicine, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands 3 Cancer Genomics Netherlands, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands Error-free chromosome segregation relies on stable and cell division. The messenger is the SAC (also known as connections between kinetochores and spindle microtu- the mitotic checkpoint) (Figure 1). bules. The spindle assembly checkpoint (SAC) monitors The transition to anaphase is triggered by the E3 ubiqui- such connections and relays their absence to the cell tin ligase APC/C, which tags inhibitors of mitotic exit cycle machinery to delay cell division. The molecular (CYCLIN B) and of sister chromatid disjunction (SECURIN) network at kinetochores that is responsible for microtu- for proteasomal degradation [2]. The SAC has a one-track bule binding is integrated with the core components mind, inhibiting APC/C as long as incorrectly attached of the SAC signaling system. Molecular-mechanistic chromosomes persist. It goes about this in the most straight- understanding of how the SAC is coupled to the kineto- forward way possible: it assembles a direct and diffusible chore–microtubule interface has advanced significantly inhibitor of APC/C at kinetochores that are not connected in recent years. The latest insights not only provide a to spindle microtubules. This inhibitor is named the striking view of the dynamics and regulation of SAC mitotic checkpoint complex (MCC) (Figure 1).
    [Show full text]
  • Bub1 Positions Mad1 Close to KNL1 MELT Repeats to Promote Checkpoint Signalling
    ARTICLE Received 14 Dec 2016 | Accepted 3 May 2017 | Published 12 June 2017 DOI: 10.1038/ncomms15822 OPEN Bub1 positions Mad1 close to KNL1 MELT repeats to promote checkpoint signalling Gang Zhang1, Thomas Kruse1, Blanca Lo´pez-Me´ndez1, Kathrine Beck Sylvestersen1, Dimitriya H. Garvanska1, Simone Schopper1, Michael Lund Nielsen1 & Jakob Nilsson1 Proper segregation of chromosomes depends on a functional spindle assembly checkpoint (SAC) and requires kinetochore localization of the Bub1 and Mad1/Mad2 checkpoint proteins. Several aspects of Mad1/Mad2 kinetochore recruitment in human cells are unclear and in particular the underlying direct interactions. Here we show that conserved domain 1 (CD1) in human Bub1 binds directly to Mad1 and a phosphorylation site exists in CD1 that stimulates Mad1 binding and SAC signalling. Importantly, fusion of minimal kinetochore-targeting Bub1 fragments to Mad1 bypasses the need for CD1, revealing that the main function of Bub1 is to position Mad1 close to KNL1 MELTrepeats. Furthermore, we identify residues in Mad1 that are critical for Mad1 functionality, but not Bub1 binding, arguing for a direct role of Mad1 in the checkpoint. This work dissects functionally relevant molecular interactions required for spindle assembly checkpoint signalling at kinetochores in human cells. 1 The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark. Correspondence and requests for materials should be addressed to G.Z.
    [Show full text]
  • The Closed Form of Mad2 Is Bound to Mad1 and Cdc20 at Unattached Kinetochores
    bioRxiv preprint doi: https://doi.org/10.1101/305763; this version posted April 21, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. The closed form of Mad2 is bound to Mad1 and Cdc20 at unattached kinetochores. Gang Zhang1,2,3 and Jakob Nilsson1 1 The Novo Nordisk Foundation Center for Protein Research, Faculty of health and medical sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark 2 Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266061, China 3 Qingdao Cancer Institute, Qingdao, Shandong 266061, China For correspondence: [email protected] or [email protected] Keywords: Mad2, Cdc20, Kinetochore, Spindle Assembly Checkpoint, Mad1 1 bioRxiv preprint doi: https://doi.org/10.1101/305763; this version posted April 21, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. ABSTRACT The spindle assembly checkpoint (SAC) ensures accurate chromosome segregation by delaying anaphase onset in response to unattached kinetochores. Anaphase is delayed by the generation of the mitotic checkpoint complex (MCC) composed of the checkpoint proteins Mad2 and BubR1/Bub3 bound to the protein Cdc20. Current models assume that MCC production is catalyzed at unattached kinetochores and that the Mad1/Mad2 complex is instrumental in the conversion of Mad2 from an open form (O-Mad2) to a closed form (C-Mad2) that can bind to Cdc20.
    [Show full text]
  • List, Describe, Diagram, and Identify the Stages of Meiosis
    Meiosis and Sexual Life Cycles Objective # 1 In this topic we will examine a second type of cell division used by eukaryotic List, describe, diagram, and cells: meiosis. identify the stages of meiosis. In addition, we will see how the 2 types of eukaryotic cell division, mitosis and meiosis, are involved in transmitting genetic information from one generation to the next during eukaryotic life cycles. 1 2 Objective 1 Objective 1 Overview of meiosis in a cell where 2N = 6 Only diploid cells can divide by meiosis. We will examine the stages of meiosis in DNA duplication a diploid cell where 2N = 6 during interphase Meiosis involves 2 consecutive cell divisions. Since the DNA is duplicated Meiosis II only prior to the first division, the final result is 4 haploid cells: Meiosis I 3 After meiosis I the cells are haploid. 4 Objective 1, Stages of Meiosis Objective 1, Stages of Meiosis Prophase I: ¾ Chromosomes condense. Because of replication during interphase, each chromosome consists of 2 sister chromatids joined by a centromere. ¾ Synapsis – the 2 members of each homologous pair of chromosomes line up side-by-side to form a tetrad consisting of 4 chromatids: 5 6 1 Objective 1, Stages of Meiosis Objective 1, Stages of Meiosis Prophase I: ¾ During synapsis, sometimes there is an exchange of homologous parts between non-sister chromatids. This exchange is called crossing over. 7 8 Objective 1, Stages of Meiosis Objective 1, Stages of Meiosis (2N=6) Prophase I: ¾ the spindle apparatus begins to form. ¾ the nuclear membrane breaks down: Prophase I 9 10 Objective 1, Stages of Meiosis Objective 1, 4 Possible Metaphase I Arrangements: Metaphase I: ¾ chromosomes line up along the equatorial plate in pairs, i.e.
    [Show full text]
  • Anaphase Bridges: Not All Natural Fibers Are Healthy
    G C A T T A C G G C A T genes Review Anaphase Bridges: Not All Natural Fibers Are Healthy Alice Finardi 1, Lucia F. Massari 2 and Rosella Visintin 1,* 1 Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, 20139 Milan, Italy; alice.fi[email protected] 2 The Wellcome Centre for Cell Biology, Institute of Cell Biology, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3BF, UK; [email protected] * Correspondence: [email protected]; Tel.: +39-02-5748-9859; Fax: +39-02-9437-5991 Received: 14 July 2020; Accepted: 5 August 2020; Published: 7 August 2020 Abstract: At each round of cell division, the DNA must be correctly duplicated and distributed between the two daughter cells to maintain genome identity. In order to achieve proper chromosome replication and segregation, sister chromatids must be recognized as such and kept together until their separation. This process of cohesion is mainly achieved through proteinaceous linkages of cohesin complexes, which are loaded on the sister chromatids as they are generated during S phase. Cohesion between sister chromatids must be fully removed at anaphase to allow chromosome segregation. Other (non-proteinaceous) sources of cohesion between sister chromatids consist of DNA linkages or sister chromatid intertwines. DNA linkages are a natural consequence of DNA replication, but must be timely resolved before chromosome segregation to avoid the arising of DNA lesions and genome instability, a hallmark of cancer development. As complete resolution of sister chromatid intertwines only occurs during chromosome segregation, it is not clear whether DNA linkages that persist in mitosis are simply an unwanted leftover or whether they have a functional role.
    [Show full text]
  • Lte1 Promotes Mitotic Exit by Controlling the Localization of the Spindle Position Checkpoint Kinase Kin4
    Lte1 promotes mitotic exit by controlling the localization of the spindle position checkpoint kinase Kin4 Jill E. Falk1, Leon Y. Chan1,2, and Angelika Amon3 David H. Koch Institute for Integrative Cancer Research and Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139 This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected in 2010. Contributed by Angelika Amon, May 17, 2011 (sent for review April 27, 2011) For a daughter cell to receive a complete genomic complement, it is The work by Adames et al. (13) proposed a model in which essential that the mitotic spindle be positioned accurately within the interactions between microtubules and the bud neck inhibit the cell. In budding yeast, a signaling system known as the spindle MEN, but how this could lead to Kin4 activation, if indeed Kin4 is position checkpoint (SPOC) monitors spindle position and regulates activated by spindle misposition, is not known. We previously the activity of the mitotic exit network (MEN), a GTPase signaling proposed a model termed the zone model, which posits that the pathway that promotes exit from mitosis. The protein kinase Kin4 budding yeast cell is divided into a MEN inhibitory zone in the is a central component of the spindle position checkpoint. Kin4 mother cell and a MEN activating zone in the daughter cell and primarily localizes to the mother cell and associates with spindle that a sensor, the GTPase Tem1, moves between them. Tem1 as well as most other components of the MEN reside at pole bodies (SPBs) located in the mother cell to inhibit MEN spindle pole bodies (SPBs; yeast centrosomes).
    [Show full text]
  • The Cell Cycle Coloring Worksheet
    Name: Date: Period: The Cell Cycle Coloring Worksheet Label the diagram below with the following labels: Anaphase Interphase Mitosis Cell division (M Phase) Interphase Prophase Cytokinesis Interphase S-DNA replication G1 – cell grows Metaphase Telophase G2 – prepares for mitosis Then on the diagram, lightly color the G1 phase BLUE, the S phase YELLOW, the G2 phase RED, and the stages of mitosis ORANGE. Color the arrows indicating all of the interphases in GREEN. Color the part of the arrow indicating mitosis PURPLE and the part of the arrow indicating cytokinesis YELLOW. M-PHASE YELLOW: GREEN: CYTOKINESIS INTERPHASE PURPLE: TELOPHASE MITOSIS ANAPHASE ORANGE METAPHASE BLUE: G1: GROWS PROPHASE PURPLE MITOSIS RED:G2: PREPARES GREEN: FOR MITOSIS INTERPHASE YELLOW: S PHASE: DNA REPLICATION GREEN: INTERPHASE Use the diagram and your notes to answer the following questions. 1. What is a series of events that cells go through as they grow and divide? CELL CYCLE 2. What is the longest stage of the cell cycle called? INTERPHASE 3. During what stage does the G1, S, and G2 phases happen? INTERPHASE 4. During what phase of the cell cycle does mitosis and cytokinesis occur? M-PHASE 5. During what phase of the cell cycle does cell division occur? MITOSIS 6. During what phase of the cell cycle is DNA replicated? S-PHASE 7. During what phase of the cell cycle does the cell grow? G1,G2 8. During what phase of the cell cycle does the cell prepare for mitosis? G2 9. How many stages are there in mitosis? 4 10. Put the following stages of mitosis in order: anaphase, prophase, metaphase, and telophase.
    [Show full text]
  • Patronus Is the Elusive Plant Securin, Preventing Chromosome Separation By
    bioRxiv preprint doi: https://doi.org/10.1101/606285; this version posted April 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Patronus is the elusive plant securin, preventing chromosome separation by 2 antagonizing separase 3 Laurence Cromer1, Sylvie Jolivet1, Dipesh Kumar Singh1, Floriane Berthier1, Nancy 4 De Winne2, Geert De Jaeger2, Shinichiro Komaki3,4, Maria Ada Prusicki3, Arp 5 Schnittger3, Raphael Guérois5 and Raphael Mercier1* 6 7 1 Institut Jean-Pierre Bourgin, UMR1318 INRA-AgroParisTech, Université Paris- 8 Saclay, RD10, 78000 Versailles, France. 9 2 Department of Plant Biotechnology and Bioinformatics, Ghent University, Ghent, 10 Belgium, VIB Center for Plant Systems Biology, Ghent, Belgium 11 3 Department of Developmental Biology, Institute for Plant Sciences and 12 Microbiology, University of Hamburg, 22609 Hamburg, Germany. 13 4 Present address : Nara Institute of Science and Technology, Graduate School of 14 Biological Sciences, 8916-5 Takayama, Ikoma, Nara 630-0192, Japan 15 5 Institute for Integrative Biology of the Cell (I2BC), Commissariat à l’Energie 16 Atomique et aux Energies Alternatives (CEA), Centre National de la Recherche 17 Scientifique (CNRS), Université Paris-Sud, CEA-Saclay, Gif-sur-Yvette, France 18 * Corresponding author. [email protected] 19 1 bioRxiv preprint doi: https://doi.org/10.1101/606285; this version posted April 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
    [Show full text]