The Centrosome pp 157-172 | Cite as

Regulation of the Centrosome Cycle by Protein Degradation



Irreversible protein destruction is a key regulatory mechanism controlling progression through the cell cycle. This is orchestrated by ubiquitin ligases, the two most prominent of which in the cell cycle are the anaphase promoting complex/cyclosome (APC/C) and the Skp1/Cullin/F-box (SCF) protein. Through targeting specific proteins for timely degradation, these complexes not only ensure accurate control of the cell cycle, but also ensure precise regulation of the centrosome duplication cycle. Disruption of the centrosome cycle can lead to formation of aberrant or supernumerary centrosomes that in turn contribute to cell division errors and genetic instability. Recent progress has revealed that protein degradation mechanisms are central to many aspects of centriole biogenesis. By strictly regulating the abundance of core centriole assembly proteins, the number of new centrioles formed within each cell cycle is tightly controlled. Moreover, protein destruction is equally important in ensuring that centrioles of the correct length are formed, while licensing of centriole duplication, which occurs during mitosis, is also controlled by protein degradation. The major ubiquitin-mediated degradation events that ensure fidelity of the centrosome cycle will be considered in this chapter.


  1. Ahmed AA et al (2010) SIK2 is a centrosome kinase required for bipolar mitotic spindle formation that provides a potential target for therapy in ovarian cancer. Cancer Cell 18:109–121PubMedCrossRefGoogle Scholar
  2. Bahe S, Stierhof YD, Wilkinson CJ, Leiss F, Nigg EA (2005) Rootletin forms centriole-associated filaments and functions in centrosome cohesion. J Cell Biol 171:27–33PubMedCrossRefGoogle Scholar
  3. Bai C et al (1996) SKP1 connects cell cycle regulators to the ubiquitin proteolysis machinery through a novel motif, the F-box. Cell 86:263–274PubMedCrossRefGoogle Scholar
  4. Bettencourt-Dias M, Glover DM (2007) Centrosome biogenesis and function: centrosomics brings new understanding. Nat Rev Mol Cell Biol 8:451–463PubMedCrossRefGoogle Scholar
  5. Bettencourt-Dias M et al (2005) SAK/PLK4 is required for centriole duplication and flagella development. Curr Biol 15:2199–2207PubMedCrossRefGoogle Scholar
  6. Brownlee CW, Klebba JE, Buster DW, Rogers GC (2011) The Protein Phosphatase 2A regulatory subunit Twins stabilizes Plk4 to induce centriole amplification. J Cell Biol 195:231–243PubMedCrossRefGoogle Scholar
  7. Cardozo T, Pagano M (2004) The SCF ubiquitin ligase: insights into a molecular machine. Nat Rev Mol Cell Biol 5:739–751PubMedCrossRefGoogle Scholar
  8. Casenghi M et al (2003) Polo-like kinase 1 regulates Nlp, a centrosome protein involved in microtubule nucleation. Dev Cell 5:113–125PubMedCrossRefGoogle Scholar
  9. Cormier A et al (2009) The PN2-3 domain of centrosomal P4.1-associated protein implements a novel mechanism for tubulin sequestration. J Biol Chem 284:6909–6917PubMedCrossRefGoogle Scholar
  10. Cunha-Ferreira I et al (2009) The SCF/Slimb ubiquitin ligase limits centrosome amplification through degradation of SAK/PLK4. Curr Biol 19:43–49PubMedCrossRefGoogle Scholar
  11. Dammermann A et al (2004) Centriole assembly requires both centriolar and pericentriolar material proteins. Dev Cell 7:815–829PubMedCrossRefGoogle Scholar
  12. D’Angiolella V et al (2010) SCF(Cyclin F) controls centrosome homeostasis and mitotic fidelity through CP110 degradation. Nature 466:138–142PubMedCrossRefGoogle Scholar
  13. Delattre M et al (2004) Centriolar SAS-5 is required for centrosome duplication in C. elegans. Nat Cell Biol 6:656–664PubMedCrossRefGoogle Scholar
  14. Delattre M, Canard C, Gonczy P (2006) Sequential protein recruitment in C. elegans centriole formation. Curr Biol 16:1844–1849PubMedCrossRefGoogle Scholar
  15. Di Fiore B, Pines J (2007) Emi1 is needed to couple DNA replication with mitosis but does not regulate activation of the mitotic APC/C. J Cell Biol 177:425–437PubMedCrossRefGoogle Scholar
  16. Eckerdt F, Yamamoto TM, Lewellyn AL, Maller JL (2011) Identification of a polo-like kinase 4-dependent pathway for de novo centriole formation. Curr Biol 21:428–432PubMedCrossRefGoogle Scholar
  17. Floyd S, Pines J, Lindon C (2008) APC/C Cdh1 targets aurora kinase to control reorganization of the mitotic spindle at anaphase. Curr Biol 18:1649–1658PubMedCrossRefGoogle Scholar
  18. Freed E et al (1999) Components of an SCF ubiquitin ligase localize to the centrosome and regulate the centrosome duplication cycle. Genes Dev 13:2242–2257PubMedCrossRefGoogle Scholar
  19. Glotzer M, Murray AW, Kirschner MW (1991) Cyclin is degraded by the ubiquitin pathway. Nature 349:132–138PubMedCrossRefGoogle Scholar
  20. Guardavaccaro D et al (2003) Control of meiotic and mitotic progression by the F box protein beta-Trcp1 in vivo. Dev Cell 4:799–812PubMedCrossRefGoogle Scholar
  21. Guderian G, Westendorf J, Uldschmid A, Nigg EA (2010) Plk4 transautophosphorylation regulates centriole number by controlling betaTrCP-mediated degradation. J Cell Sci 123:2163–2169PubMedCrossRefGoogle Scholar
  22. Habedanck R, Stierhof YD, Wilkinson CJ, Nigg EA (2005) The Polo kinase Plk4 functions in centriole duplication. Nat Cell Biol 7:1140–1146PubMedCrossRefGoogle Scholar
  23. Hansen DV, Loktev AV, Ban KH, Jackson PK (2004) Plk1 regulates activation of the anaphase promoting complex by phosphorylating and triggering SCFbetaTrCP-dependent destruction of the APC Inhibitor Emi1. Mol Biol Cell 15:5623–5634PubMedCrossRefGoogle Scholar
  24. Haren L, Stearns T, Luders J (2009) Plk1-dependent recruitment of gamma-tubulin complexes to mitotic centrosomes involves multiple PCM components. PLoS ONE 4:e5976PubMedCrossRefGoogle Scholar
  25. Hatch EM, Kulukian A, Holland AJ, Cleveland DW, Stearns T (2010) Cep152 interacts with Plk4 and is required for centriole duplication. J Cell Biol 191:721–729PubMedCrossRefGoogle Scholar
  26. Hayes MJ et al (2006) Early mitotic degradation of Nek2A depends on Cdc20-independent interaction with the APC/C. Nat Cell Biol 8:607–614PubMedCrossRefGoogle Scholar
  27. Hershko A, Ciechanover A (1998) The ubiquitin system. Annu Rev Biochem 67:425–479PubMedCrossRefGoogle Scholar
  28. Hinchcliffe, EH, Li, C, Thompson, EA, Maller, JL, Sluder, G (1999) Requirement of Cdk2-cyclin E activity for repeated centrosome reproduction in Xenopus egg extracts. Science 283:851–854Google Scholar
  29. Hiraki M, Nakazawa Y, Kamiya R, Hirono M (2007) Bld10p constitutes the cartwheel spoke tip and stabilizes the 9-fold symmetry of the centriole. Curr Biol 17:1778–1783PubMedCrossRefGoogle Scholar
  30. Holland AJ, Lan W, Niessen S, Hoover H, Cleveland DW (2010) Polo-like kinase 4 kinase activity limits centrosome overduplication by autoregulating its own stability. J Cell Biol 188:191–198PubMedCrossRefGoogle Scholar
  31. Hsu WB et al (2008) Functional characterization of the microtubule-binding and -destabilizing domains of CPAP and d-SAS-4. Exp Cell Res 314:2591–2602PubMedCrossRefGoogle Scholar
  32. Kettenbach, AN et al (2011) Quantitative phosphoproteomics identifies substrates and functional modules of Aurora and Polo-like kinase activities in mitotic cells. Sci Signal 4, rs5Google Scholar
  33. Khodjakov A, Rieder CL (1999) The sudden recruitment of gamma-tubulin to the centrosome at the onset of mitosis and its dynamic exchange throughout the cell cycle, do not require microtubules. J Cell Biol 146:585–596PubMedCrossRefGoogle Scholar
  34. Kim HS et al (2011) SIRT2 maintains genome integrity and suppresses tumorigenesis through regulating APC/C activity. Cancer Cell 20:487–499PubMedCrossRefGoogle Scholar
  35. Kimata Y, Baxter JE, Fry AM, Yamano H (2008) A role for the Fizzy/Cdc20 family of proteins in activation of the APC/C distinct from substrate recruitment. Mol Cell 32:576–583PubMedCrossRefGoogle Scholar
  36. Kitagawa D, Busso C, Fluckiger I, Gonczy P (2009) Phosphorylation of SAS-6 by ZYG-1 is critical for centriole formation in C. elegans embryos. Dev Cell 17:900–907PubMedCrossRefGoogle Scholar
  37. Kitagawa D et al (2011) Structural basis of the 9-fold symmetry of centrioles. Cell 144:364–375PubMedCrossRefGoogle Scholar
  38. Kleylein-Sohn J et al (2007) Plk4-induced centriole biogenesis in human cells. Dev Cell 13:190–202PubMedCrossRefGoogle Scholar
  39. Kobayashi T, Dynlacht BD (2011) Regulating the transition from centriole to basal body. J Cell Biol 193:435–444PubMedCrossRefGoogle Scholar
  40. Kohlmaier G et al (2009) Overly long centrioles and defective cell division upon excess of the SAS-4-related protein CPAP. Curr Biol 19:1012–1018PubMedCrossRefGoogle Scholar
  41. Korzeniewski N, Cuevas R, Duensing A, Duensing S (2010) Daughter centriole elongation is controlled by proteolysis. Mol Biol Cell 21:3942–3951PubMedCrossRefGoogle Scholar
  42. Lacey KR, Jackson PK, Stearns T (1999) Cyclin-dependent kinase control of centrosome duplication. Proc Nat Acad Sci U S A 96:2817–2822CrossRefGoogle Scholar
  43. Leidel S, Delattre M, Cerutti L, Baumer K, Gonczy P (2005) SAS-6 defines a protein family required for centrosome duplication in C. elegans and in human cells. Nat Cell Biol 7:115–125PubMedCrossRefGoogle Scholar
  44. Lindon C, Pines J (2004) Ordered proteolysis in anaphase inactivates Plk1 to contribute to proper mitotic exit in human cells. J Cell Biol 164:233–241PubMedCrossRefGoogle Scholar
  45. Loncarek J, Khodjakov A (2009) Ab ovo or de novo? Mechanisms of centriole duplication. Mol Cells 27:135–142PubMedCrossRefGoogle Scholar
  46. Loncarek J, Hergert P, Khodjakov A (2010) Centriole reduplication during prolonged interphase requires procentriole maturation governed by Plk1. Curr Biol 20:1277–1282PubMedCrossRefGoogle Scholar
  47. Mardin BR et al (2010) Components of the Hippo pathway cooperate with Nek2 kinase to regulate centrosome disjunction. Nat Cell Biol 12:1166–1176PubMedCrossRefGoogle Scholar
  48. Mardin BR, Agircan FG, Lange C, Schiebel E (2011) Plk1 controls the Nek2APP1gamma antagonism in centrosome disjunction. Curr Biol 21:1145–1151PubMedCrossRefGoogle Scholar
  49. Mathe E et al (2004) The E2-C vihar is required for the correct spatiotemporal proteolysis of cyclin B and itself undergoes cyclical degradation. Curr Biol 14:1723–1733PubMedCrossRefGoogle Scholar
  50. Matsuo K, Ohsumi K, Iwabuchi M, Kawamata T, Ono Y, Takahashi M (2012) Kendrin is a novel substrate for separase involved in the licensing of centriole duplication. Curr Biol 22 (in press)Google Scholar
  51. Matsumoto Y, Hayashi K, Nishida E (1999) Cyclin-dependent kinase 2 (Cdk2) is required for centrosome duplication in mammalian cells. Curr Biol 9:429–432PubMedCrossRefGoogle Scholar
  52. Mayor T, Hacker U, Stierhof YD, Nigg EA (2002) The mechanism regulating the dissociation of the centrosomal protein C-Nap1 from mitotic spindle poles. J Cell Sci 115:3275–3284PubMedGoogle Scholar
  53. Meraldi P, Lukas J, Fry AM, Bartek J, Nigg EA (1999) Centrosome duplication in mammalian somatic cells requires E2F and Cdk2-cyclin A. Nat Cell Biol 1:88–93PubMedCrossRefGoogle Scholar
  54. Moshe Y, Boulaire J, Pagano M, Hershko A (2004) Role of Polo-like kinase in the degradation of early mitotic inhibitor 1, a regulator of the anaphase promoting complex/cyclosome. Proc Natl Acad Sci U S A 101:7937–7942PubMedCrossRefGoogle Scholar
  55. Murray AW (2004) Recycling the cell cycle: cyclins revisited. Cell 116:221–234PubMedCrossRefGoogle Scholar
  56. Nakazawa Y, Hiraki M, Kamiya R, Hirono M (2007) SAS-6 is a cartwheel protein that establishes the 9-fold symmetry of the centriole. Curr Biol 17:2169–2174PubMedCrossRefGoogle Scholar
  57. Nasmyth K (2011) Cohesin: a catenase with separate entry and exit gates? Nat Cell Biol 13:1170–1177PubMedCrossRefGoogle Scholar
  58. Nigg EA (2007) Centrosome duplication: of rules and licenses. Trends Cell Biol 17:215–221PubMedCrossRefGoogle Scholar
  59. Nigg EA, Stearns T (2011) The centrosome cycle: centriole biogenesis, duplication and inherent asymmetries. Nat Cell Biol 13:1154–1160PubMedCrossRefGoogle Scholar
  60. Nurse P (2000) A long twentieth century of the cell cycle and beyond. Cell 100:71–78PubMedCrossRefGoogle Scholar
  61. O’Regan L, Blot J, Fry AM (2007) Mitotic regulation by NIMA-related kinases. Cell Div 2:25PubMedCrossRefGoogle Scholar
  62. Peel N, Stevens NR, Basto R, Raff JW (2007) Overexpressing centriole-replication proteins in vivo induces centriole overduplication and de novo formation. Curr Biol 17:834–843PubMedCrossRefGoogle Scholar
  63. Pelletier L, O’Toole E, Schwager A, Hyman AA, Muller-Reichert T (2006) Centriole assembly in Caenorhabditis elegans. Nature 444:619–623PubMedCrossRefGoogle Scholar
  64. Peters JM (2006) The anaphase promoting complex/cyclosome: a machine designed to destroy. Nat Rev Mol Cell Biol 7:644–656PubMedCrossRefGoogle Scholar
  65. Peters JM, Tedeschi A, Schmitz J (2008) The cohesin complex and its roles in chromosome biology. Genes Dev 22:3089–3114PubMedCrossRefGoogle Scholar
  66. Prosser SL, Samant M, Baxter JE, Morrison CG, Fry AM (2012) Oscillation of APC/C activity during cell cycle arrest promotes centrosome amplification (under revision)Google Scholar
  67. Puklowski A et al (2011) The SCF-FBXW5 E3-ubiquitin ligase is regulated by PLK4 and targets HsSAS-6 to control centrosome duplication. Nat Cell Biol 13:1004–1009PubMedCrossRefGoogle Scholar
  68. Raff JW, Jeffers K, Huang JY (2002) The roles of Fzy/Cdc20 and Fzr/Cdh1 in regulating the destruction of cyclin B in space and time. J Cell Biol 157:1139–1149PubMedCrossRefGoogle Scholar
  69. Rapley J et al (2005) Coordinate regulation of the mother centriole component nlp by nek2 and plk1 protein kinases. Mol Cell Biol 25:1309–1324PubMedCrossRefGoogle Scholar
  70. Rodrigues-Martins A, Riparbelli M, Callaini G, Glover DM, Bettencourt-Dias M (2007) Revisiting the role of the mother centriole in centriole biogenesis. Science 316:1046–1050PubMedCrossRefGoogle Scholar
  71. Rogers GC, Rusan NM, Roberts DM, Peifer M, Rogers SL (2009) The SCF Slimb ubiquitin ligase regulates Plk4/Sak levels to block centriole reduplication. J Cell Biol 184:225–239PubMedCrossRefGoogle Scholar
  72. Rosario CO et al (2010) Plk4 is required for cytokinesis and maintenance of chromosomal stability. Proc Natl Acad Sci U S A 107:6888–6893PubMedCrossRefGoogle Scholar
  73. Schmidt TI et al (2009) Control of centriole length by CPAP and CP110. Curr Biol 19:1005–1011PubMedCrossRefGoogle Scholar
  74. Schockel L, Mockel M, Mayer B, Boos D, Stemmann O (2011) Cleavage of cohesin rings coordinates the separation of centrioles and chromatids. Nat Cell Biol 13:966–972PubMedCrossRefGoogle Scholar
  75. Skaar JR, Pagano M (2009) Control of cell growth by the SCF and APC/C ubiquitin ligases. Curr Opin Cell Biol 21:816–824PubMedCrossRefGoogle Scholar
  76. Song MH, Liu Y, Anderson DE, Jahng WJ, O’Connell KF (2011) Protein phosphatase 2A-SUR-6/B55 regulates centriole duplication in C. elegans by controlling the levels of centriole assembly factors. Dev Cell 20:563–571PubMedCrossRefGoogle Scholar
  77. Spektor A, Tsang WY, Khoo D, Dynlacht BD (2007) Cep97 and CP110 suppress a cilia assembly program. Cell 130:678–690PubMedCrossRefGoogle Scholar
  78. Steere N et al (2011) Centrosome amplification in CHO and DT40 cells by inactivation of cyclin-dependent kinases. Cytoskeleton (Hoboken) 68:446–458Google Scholar
  79. Stevens NR, Dobbelaere J, Brunk K, Franz A, Raff JW (2010) Drosophila Ana2 is a conserved centriole duplication factor. J Cell Biol 188:313–323PubMedCrossRefGoogle Scholar
  80. Strnad P, Gonczy P (2008) Mechanisms of procentriole formation. Trends Cell Biol 18:389–396PubMedCrossRefGoogle Scholar
  81. Strnad P et al (2007) Regulated HsSAS-6 levels ensure formation of a single procentriole per centriole during the centrosome duplication cycle. Dev Cell 13:203–213PubMedCrossRefGoogle Scholar
  82. Tang CJ, Fu RH, Wu KS, Hsu WB, Tang TK (2009) CPAP is a cell-cycle regulated protein that controls centriole length. Nat Cell Biol 11:825–831PubMedCrossRefGoogle Scholar
  83. Tang CJ et al (2011) The human microcephaly protein STIL interacts with CPAP and is required for procentriole formation. EMBO J 30:4790–4804PubMedCrossRefGoogle Scholar
  84. Thein KH, Kleylein-Sohn J, Nigg EA, Gruneberg U (2007) Astrin is required for the maintenance of sister chromatid cohesion and centrosome integrity. J Cell Biol 178:345–354PubMedCrossRefGoogle Scholar
  85. Tsou MF, Stearns T (2006a) Controlling centrosome number: licenses and blocks. Curr Opin Cell Biol 18:74–78PubMedCrossRefGoogle Scholar
  86. Tsou MF, Stearns T (2006b) Mechanism limiting centrosome duplication to once per cell cycle. Nature 442:947–951PubMedCrossRefGoogle Scholar
  87. Tsou MF et al (2009) Polo kinase and separase regulate the mitotic licensing of centriole duplication in human cells. Dev Cell 17:344–354PubMedCrossRefGoogle Scholar
  88. van Breugel M et al (2011) Structures of SAS-6 suggest its organization in centrioles. Science 331:1196–1199PubMedCrossRefGoogle Scholar
  89. Vidwans SJ, Wong ML, O’Farrell PH (2003) Anomalous centriole configurations are detected in Drosophila wing disc cells upon Cdk1 inactivation. J Cell Sci 116:137–143PubMedCrossRefGoogle Scholar
  90. Wang, LY, Kung, HJ (2011) Male germ cell-associated kinase is overexpressed in prostate cancer cells and causes mitotic defects via deregulation of APC/C(CDH1). OncogeneGoogle Scholar
  91. Wang Y, Zhan Q (2007) Cell cycle-dependent expression of centrosomal ninein-like protein in human cells is regulated by the anaphase-promoting complex. J Biol Chem 282:17712–17719PubMedCrossRefGoogle Scholar
  92. Wojcik EJ, Glover DM, Hays TS (2000) The SCF ubiquitin ligase protein slimb regulates centrosome duplication in Drosophila. Curr Biol 10:1131–1134PubMedCrossRefGoogle Scholar
  93. Zhao X, Jin S, Song Y, Zhan Q (2010) Cdc2/cyclin B1 regulates centrosomal Nlp proteolysis and subcellular localization. Cancer Biol Ther 10:945–952PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press, a part of Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of BiochemistryUniversity of LeicesterLeicesterUK

Personalised recommendations