The anaphase promoting complex/cyclosome: a machine designed to destroy

Key Points

  • The anaphase promoting complex/cyclosome (APC/C) is a 1.5-MDa ubiquitin ligase complex that initiates sister-chromatid separation and exit from mitosis by targeting cyclin B and securin for destruction by the 26S proteasome.

  • APC/C activity is also indirectly required for DNA replication, because APC/C-mediated cyclin degradation leads to the inactivation of cyclin-dependent kinase-1 (Cdk1), which is a prerequisite for the assembly of pre-replication complexes.

  • APC/C is activated by proteins of the Cdc20/Cdh1 family. The interaction between APC/C and its co-activators is tightly controlled by phosphorylation and is restricted to mitosis and G1 phase.

  • In addition, APC/C activity can be restrained by a number of inhibitory proteins. Mad2 and BubR1 inhibit APC/C during spindle assembly and thereby prevent precocious initiation of anaphase and exit from mitosis. Members of the early mitotic inhibitor-1 (EMI1)/regulator of cyclin A-1 (RCA1) family inhibit APC/C from S phase until early mitosis and during meiosis in vertebrate eggs.

  • Co-activator proteins activate APC/C by facilitating the recruitment of substrates. All known APC/C co-activators contain a propeller-shaped WD40 domain that interacts with a recognition element in APC/C substrates and is known as the destruction box (D-box).

  • Co-activators are required but not sufficient for substrate recognition because the APC/C subunit Doc1 is also needed for this process. Several observations suggest that the D-box of substrates might interact with both co-activators and APC/C subunits to form a ternary complex in which substrate ubiquitylation occurs.


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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: The three-dimensional structure of APC/C.
Figure 2: Regulation of anaphase and mitotic exit by APC/CCdc20.
Figure 3: Activation of APC/C by Cdc20 and Cdh1 during the cell cycle.
Figure 4: Inactivation of APC/CCdh1 at the transition from G1 to S phase.
Figure 5: Activation of Mad2 at unattached kinetochores.


  1. 1

    Peters, J. M. The anaphase-promoting complex: proteolysis in mitosis and beyond. Mol. Cell 9, 931–943 (2002).

    CAS  PubMed  Google Scholar 

  2. 2

    Harper, J. W., Burton, J. L. & Solomon, M. J. The anaphase-promoting complex: it's not just for mitosis any more. Genes Dev. 16, 2179–2206 (2002).

    CAS  PubMed  Google Scholar 

  3. 3

    Aristarkhov, A. et al. E2-C, a cyclin-selective ubiquitin carrier protein required for the destruction of mitotic cyclins. Proc. Natl Acad. Sci. USA 93, 4294–4299 (1996).

    CAS  PubMed  Google Scholar 

  4. 4

    Yu, H., King, R. W., Peters, J. M. & Kirschner, M. W. Identification of a novel ubiquitin-conjugating enzyme involved in mitotic cyclin degradation. Curr. Biol. 6, 455–466 (1996).

    CAS  PubMed  Google Scholar 

  5. 5

    Townsley, F. M., Aristarkhov, A., Beck, S., Hershko, A. & Ruderman, J. V. Dominant-negative cyclin-selective ubiquitin carrier protein E2-C/UbcH10 blocks cells in metaphase. Proc. Natl Acad. Sci. USA 94, 2362–2367 (1997).

    CAS  PubMed  Google Scholar 

  6. 6

    Seino, H., Kishi, T., Nishitani, H. & Yamao, F. Two ubiquitin-conjugating enzymes, UbcP1/Ubc4 and UbcP4/Ubc11, have distinct functions for ubiquitination of mitotic cyclin. Mol. Cell. Biol. 23, 3497–3505 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Mathe, E. et al. The E2-C vihar is required for the correct spatiotemporal proteolysis of cyclin B and itself undergoes cyclical degradation. Curr. Biol. 14, 1723–1733 (2004).

    CAS  PubMed  Google Scholar 

  8. 8

    Townsley, F. M. & Ruderman, J. V. Functional analysis of the Saccharomyces cerevisiae UBC11 gene. Yeast 14, 747–757 (1998).

    CAS  PubMed  Google Scholar 

  9. 9

    Carroll, C. W. & Morgan, D. O. The Doc1 subunit is a processivity factor for the anaphase-promoting complex. Nature Cell Biol. 4, 880–887 (2002). Shows that the processivity of APC/C-mediated ubiquitylation reactions depends on Doc1.

    CAS  PubMed  Google Scholar 

  10. 10

    Deffenbaugh, A. E. et al. Release of ubiquitin-charged Cdc34–S Ub from the RING domain is essential for ubiquitination of the SCFCdc4-bound substrate Sic1. Cell 114, 611–622 (2003).

    CAS  PubMed  Google Scholar 

  11. 11

    Schwab, M., Neutzner, M., Mocker, D. & Seufert, W. Yeast Hct1 recognizes the mitotic cyclin Clb2 and other substrates of the ubiquitin ligase APC. EMBO J. 20, 5165–5175 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Passmore, L. A. et al. Doc1 mediates the activity of the anaphase-promoting complex by contributing to substrate recognition. EMBO J. 22, 786–796 (2003). Shows that co-activators are required but are not sufficient for stable substrate–APC/C interactions, and that Doc1 is also needed for these interactions.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Vodermaier, H. C., Gieffers, C., Maurer-Stroh, S., Eisenhaber, F. & Peters, J. M. TPR subunits of the anaphase-promoting complex mediate binding to the activator protein CDH1. Curr. Biol. 13, 1459–1468 (2003).

    CAS  PubMed  Google Scholar 

  14. 14

    Kraft, C., Vodermaier, H. C., Maurer-Stroh, S., Eisenhaber, F. & Peters, J. M. The WD40 propeller domain of Cdh1 functions as a destruction box receptor for APC/C substrates. Mol. Cell 18, 543–553 (2005). Shows that the D-box of APC/C substrates binds directly to the WD40 domain of Cdh1 and provides evidence that this interaction is required for processive substrate ubiquitylation.

    CAS  PubMed  Google Scholar 

  15. 15

    Glotzer, M., Murray, A. W. & Kirschner, M. W. Cyclin is degraded by the ubiquitin pathway. Nature 349, 132–138 (1991).

    CAS  PubMed  Google Scholar 

  16. 16

    Pfleger, C. M. & Kirschner, M. W. The KEN box: an APC recognition signal distinct from the D box targeted by Cdh1. Genes Dev. 14, 655–665 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Kramer, K. M., Fesquet, D., Johnson, A. L. & Johnston, L. H. Budding yeast RSI1/APC2, a novel gene necessary for initiation of anaphase, encodes an APC subunit. EMBO J. 17, 498–506 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Yu, H. et al. Identification of a cullin homology region in a subunit of the anaphase-promoting complex. Science 279, 1219–1222 (1998).

    CAS  PubMed  Google Scholar 

  19. 19

    Zachariae, W. et al. Mass spectrometric analysis of the anaphase promoting complex from yeast: identification of a subunit related to cullins. Science 279, 1216–1219 (1998).

    CAS  PubMed  Google Scholar 

  20. 20

    Tang, Z. et al. APC2 cullin protein and APC11 RING protein comprise the minimal ubiquitin ligase module of the anaphase-promoting complex. Mol. Biol. Cell 12, 3839–3851 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Gmachl, M., Gieffers, C., Podtelejnikov, A. V., Mann, M. & Peters, J. M. The RING-H2 finger protein APC11 and the E2 enzyme UBC4 are sufficient to ubiquitinate substrates of the anaphase-promoting complex. Proc. Natl Acad. Sci. USA 97, 8973–8978 (2000).

    CAS  PubMed  Google Scholar 

  22. 22

    Leverson, J. D. et al. The APC11 RING-H2 finger mediates E2-dependent ubiquitination. Mol. Biol. Cell 11, 2315–2325 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Passmore, L. A. & Barford, D. Getting into position: the catalytic mechanisms of protein ubiquitylation. Biochem. J. 379, 513–525 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Petroski, M. D. & Deshaies, R. J. Function and regulation of cullin–RING ubiquitin ligases. Nature Rev. Mol. Cell Biol. 6, 9–20 (2005).

    CAS  Google Scholar 

  25. 25

    Sudakin, V. et al. The cyclosome, a large complex containing cyclin-selective ubiquitin ligase activity, targets cyclins for destruction at the end of mitosis. Mol. Biol. Cell 6, 185–198 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Dube, P. et al. Localization of the coactivator Cdh1 and the cullin subunit Apc2 in a cryo-electron microscopy model of vertebrate APC/C. Mol. Cell 20, 867–879 (2005). Provides first insight into where in the vertebrate APC/C structure substrates might be ubiquitylated.

    CAS  PubMed  Google Scholar 

  27. 27

    Gieffers, C., Dube, P., Harris, J. R., Stark, H. & Peters, J. M. Three-dimensional structure of the anaphase-promoting complex. Mol. Cell 7, 907–913 (2001).

    CAS  PubMed  Google Scholar 

  28. 28

    Passmore, L. A. et al. Structural analysis of the anaphase-promoting complex reveals multiple active sites and insights into polyubiquitylation. Mol. Cell 20, 855–866 (2005). Shows first EM structures of budding yeast APC/C and provides evidence that APC/C might have to dimerize to be fully active.

    CAS  PubMed  Google Scholar 

  29. 29

    Schwickart, M. et al. Swm1/Apc13 is an evolutionarily conserved subunit of the anaphase-promoting complex stabilizing the association of Cdc16 and Cdc27. Mol. Cell. Biol. 24, 3562–3576 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Thornton, B. R. et al. An architectural map of the anaphase-promoting complex. Genes Dev. 20, 449–460 (2006). Provides a detailed map of how APC/C subunits interact with each other.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Schwab, M., Lutum, A. S., Seufert, W. Yeast Hct1 is a regulator of Clb2 cyclin proteolysis. Cell 90, 683–693 (1997).

    CAS  PubMed  Google Scholar 

  32. 32

    Visintin, R., Prinz, S. & Amon, A. CDC20 and CDH1: a family of substrate-specific activators of APC-dependent proteolysis. Science 278, 460–463 (1997).

    CAS  PubMed  Google Scholar 

  33. 33

    Wan, Y. & Kirschner, M. W. Identification of multiple CDH1 homologues in vertebrates conferring different substrate specificities. Proc. Natl Acad. Sci. USA 98, 13066–13071 (2001).

    CAS  PubMed  Google Scholar 

  34. 34

    Ohtoshi, A., Maeda, T., Higashi, H., Ashizawa, S. & Hatakeyama, M. Human p55CDC/Cdc20 associates with cyclin A and is phosphorylated by the cyclin A–Cdk2 complex. Biochem. Biophys. Res. Commun. 268, 530–534 (2000).

    CAS  PubMed  Google Scholar 

  35. 35

    Burton, J. L. & Solomon, M. J. D box and KEN box motifs in budding yeast Hsl1p are required for APC-mediated degradation and direct binding to Cdc20p and Cdh1p. Genes Dev. 15, 2381–2395 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Hilioti, Z., Chung, Y. S., Mochizuki, Y., Hardy, C. F. & Cohen-Fix, O. The anaphase inhibitor Pds1 binds to the APC/C-associated protein Cdc20 in a destruction box-dependent manner. Curr. Biol. 11, 1347–1352 (2001).

    CAS  PubMed  Google Scholar 

  37. 37

    Pfleger, C. M., Lee, E. & Kirschner, M. W. Substrate recognition by the Cdc20 and Cdh1 components of the anaphase-promoting complex. Genes Dev. 15, 2396–2407 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Sorensen, C. S. et al. A conserved cyclin-binding domain determines functional interplay between anaphase-promoting complex–Cdh1 and cyclin A–Cdk2 during cell cycle progression. Mol. Cell. Biol. 21, 3692–3703 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Yamano, H., Gannon, J., Mahbubani, H. & Hunt, T. Cell cycle-regulated recognition of the destruction box of cyclin B by the APC/C in Xenopus egg extracts. Mol. Cell 13, 137–147 (2004). Shows that substrates can interact directly with APC/C in a D-box-dependent manner.

    CAS  PubMed  Google Scholar 

  40. 40

    Hayes, M. J. et al. Early mitotic degradation of Nek2A depends on Cdc20-independent interaction with the APC/C. Nature Cell Biol. 8, 607–614 (2006).

    CAS  PubMed  Google Scholar 

  41. 41

    Passmore, L. A. & Barford, D. Coactivator functions in a stoichiometric complex with anaphase-promoting complex/cyclosome to mediate substrate recognition. EMBO Rep. 6, 873–878 (2005). Provides the first direct evidence for a ternary complex between APC/C, co-activator and substrate.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Burton, J. L., Tsakraklides, V. & Solomon, M. J. Assembly of an APC–Cdh1–substrate complex is stimulated by engagement of a destruction box. Mol. Cell 18, 533–542 (2005).

    CAS  PubMed  Google Scholar 

  43. 43

    Carroll, C. W., Enquist-Newman, M. & Morgan, D. O. The APC subunit Doc1 promotes recognition of the substrate destruction box. Curr. Biol. 15, 11–18 (2005).

    CAS  PubMed  Google Scholar 

  44. 44

    Eytan, E., Moshe, Y., Braunstein, I. & Hershko, A. Roles of the anaphase-promoting complex/cyclosome and of its activator Cdc20 in functional substrate binding. Proc. Natl Acad. Sci. USA 103, 2081–2086 (2006).

    CAS  PubMed  Google Scholar 

  45. 45

    Wendt, K. S. et al. Crystal structure of the APC10/DOC1 subunit of the human anaphase-promoting complex. Nature Struct. Biol. 8, 784–788 (2001).

    CAS  PubMed  Google Scholar 

  46. 46

    Au, S. W., Leng, X., Harper, J. W. & Barford, D. Implications for the ubiquitination reaction of the anaphase-promoting complex from the crystal structure of the Doc1/Apc10 subunit. J. Mol. Biol. 316, 955–968 (2002).

    CAS  PubMed  Google Scholar 

  47. 47

    Kominami, K.-i., Seth-Smith, H. & Toda, T. Apc10 and Ste9/Srw1, two regulators of the APC/cyclosome, as well as the CDK inhibitor Rum1 are required for G1-cell cycle arrest in fission yeast. EMBO J. 17, 5388–5399 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Grossberger, R. et al. Characterization of the DOC1/APC10 subunit of the yeast and the human anaphase-promoting complex. J. Biol. Chem. 274, 14500–14507 (1999).

    CAS  PubMed  Google Scholar 

  49. 49

    Gaskell, A., Crennell, S. & Taylor, G. The three domains of a bacterial sialidase: a β-propeller, an immunoglobulin module and a galactose-binding jelly-roll. Structure 3, 1197–1205 (1995).

    CAS  PubMed  Google Scholar 

  50. 50

    Irniger, S., Piatti, S., Michaelis, C. & Nasmyth, K. Genes involved in sister chromatid separation are needed for B-type cyclin proteolysis in budding yeast. Cell 81, 269–278 (1995).

    CAS  PubMed  Google Scholar 

  51. 51

    King, R. W. et al. A 20S complex containing CDC27 and CDC16 catalyzes the mitosis-specific conjugation of ubiquitin to cyclin B. Cell 81, 279–288 (1995).

    CAS  PubMed  Google Scholar 

  52. 52

    Clute, P. & Pines, J. Temporal and spatial control of cyclin B1 destruction in metaphase. Nature Cell Biol. 1, 82–87 (1999).

    CAS  PubMed  Google Scholar 

  53. 53

    Murray, A. W., Solomon, M. J. & Kirschner, M. W. The role of cyclin synthesis and degradation in the control of maturation promoting factor activity. Nature 339, 280–286 (1989).

    CAS  PubMed  Google Scholar 

  54. 54

    King, R. W., Glotzer, M. & Kirschner, M. W. Mutagenic analysis of the destruction signal of mitotic cyclins and structural characterization of ubiquitinated intermediates. Mol. Biol. Cell 7, 1343–1357 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Jeffrey, P. D. et al. Mechanism of CDK activation revealed by the structure of a cyclinA–CDK2 complex. Nature 376, 313–320 (1995).

    CAS  PubMed  Google Scholar 

  56. 56

    Diffley, J. F. Regulation of early events in chromosome replication. Curr. Biol. 14, R778–R786 (2004).

    CAS  PubMed  Google Scholar 

  57. 57

    McGarry, T. J. & Kirschner, M. W. Geminin, an inhibitor of DNA replication, is degraded during mitosis. Cell 93, 1043–1053 (1998).

    CAS  PubMed  Google Scholar 

  58. 58

    Wohlschlegel, J. A. et al. Inhibition of eukaryotic DNA replication by geminin binding to Cdt1. Science 290, 2309–2312 (2000).

    CAS  PubMed  Google Scholar 

  59. 59

    Tada, S., Li, A., Maiorano, D., Mechali, M. & Blow, J. J. Repression of origin assembly in metaphase depends on inhibition of RLF-B/Cdt1 by geminin. Nature Cell Biol. 3, 107–113 (2001).

    CAS  PubMed  Google Scholar 

  60. 60

    Quinn, L. M., Herr, A., McGarry, T. J. & Richardson, H. The Drosophila Geminin homolog: roles for Geminin in limiting DNA replication, in anaphase and in neurogenesis. Genes Dev. 15, 2741–2754 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Nasmyth, K. Disseminating the genome: joining, resolving, and separating sister chromatids during mitosis and meiosis. Annu. Rev. Genet. 35, 673–745 (2001).

    CAS  Google Scholar 

  62. 62

    Yamamoto, A., Guacci, V. & Koshland, D. Pds1p is required for faithful execution of anaphase in the yeast, Saccharomyces cerevisiae. J. Cell Biol. 133, 85–97 (1996).

    CAS  PubMed  Google Scholar 

  63. 63

    Jallepalli, P. V. et al. Securin is required for chromosomal stability in human cells. Cell 105, 445–457 (2001).

    CAS  PubMed  Google Scholar 

  64. 64

    Mei, J., Huang, X. & Zhang, P. Securin is not required for cellular viability, but is required for normal growth of mouse embryonic fibroblasts. Curr. Biol. 11, 1197–1201 (2001).

    CAS  PubMed  Google Scholar 

  65. 65

    Wang, Z., Yu, R. & Melmed, S. Mice lacking pituitary tumor transforming gene show testicular and splenic hypoplasia, thymic hyperplasia, thrombocytopenia, aberrant cell cycle progression, and premature centromere division. Mol. Endocrinol. 15, 1870–1879 (2001).

    CAS  PubMed  Google Scholar 

  66. 66

    Stemmann, O., Zou, H., Gerber, S. A., Gygi, S. P. & Kirschner, M. W. Dual inhibition of sister chromatid separation at metaphase. Cell 107, 715–726 (2001).

    CAS  PubMed  Google Scholar 

  67. 67

    Gorr, I. H., Boos, D. & Stemmann, O. Mutual inhibition of separase and Cdk1 by two-step complex formation. Mol. Cell 19, 135–141 (2005).

    CAS  PubMed  Google Scholar 

  68. 68

    Wirth, K. G. et al. Loss of the anaphase-promoting complex in quiescent cells causes unscheduled hepatocyte proliferation. Genes Dev. 18, 88–98 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Thornton, B. R. & Toczyski, D. P. Securin and B-cyclin/CDK are the only essential targets of the APC. Nature Cell Biol. 5, 1090–1094 (2003). Describes a strategy to generate yeast strains that can live without otherwise essential APC/C subunits.

    CAS  PubMed  Google Scholar 

  70. 70

    Shirayama, M., Toth, A., Galova, M. & Nasmyth, K. APCCdc20 promotes exit from mitosis by destroying the anaphase inhibitor Pds1 and cyclin Clb5. Nature 402, 203–207 (1999).

    CAS  PubMed  Google Scholar 

  71. 71

    Shteinberg, M., Protopopov, Y., Listovsky, T., Brandeis, M. & Hershko, A. Phosphorylation of the cyclosome is required for its stimulation by Fizzy/Cdc20. Biochem. Biophys. Res. Commun. 260, 193–198 (1999).

    CAS  PubMed  Google Scholar 

  72. 72

    Kramer, E. R., Scheuringer, N., Podtelejnikov, A. V., Mann, M. & Peters, J. M. Mitotic regulation of the APC activator proteins CDC20 and CDH1. Mol. Biol. Cell 11, 1555–1569 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Rudner, A. D. & Murray, A. W. Phosphorylation by Cdc28 activates the Cdc20-dependent activity of the anaphase-promoting complex. J. Cell Biol. 149, 1377–1390 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Golan, A., Yudkovsky, Y. & Hershko, A. The cyclin-ubiquitin ligase activity of cyclosome/APC is jointly activated by protein kinases Cdk1–cyclin B and Plk. J. Biol. Chem. 277, 15552–15557 (2002).

    CAS  PubMed  Google Scholar 

  75. 75

    Kraft, C. et al. Mitotic regulation of the human anaphase-promoting complex by phosphorylation. EMBO J. 22, 6598–6609 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Zachariae, W., Schwab, M., Nasmyth, K. & Seufert, W. Control of cyclin ubiquitination by CDK-regulated binding of Hct1 to the anaphase promoting complex. Science 282, 1721–1724 (1998).

    CAS  PubMed  Google Scholar 

  77. 77

    Jaspersen, S. L., Charles, J. F. & Morgan, D. O. Inhibitory phosphorylation of the APC regulator Hct1 is controlled by the kinase Cdc28 and the phosphatase Cdc14. Curr. Biol. 9, 227–236 (1999).

    CAS  PubMed  Google Scholar 

  78. 78

    Blanco, M. A., Sanchez-Diaz, A., de Prada, J. M. & Moreno, S. APCSte9/Srw1 promotes degradation of mitotic cyclins in G1 and is inhibited by Cdc2 phosphorylation. EMBO J. 19, 3945–3955 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Yamaguchi, S., Okayama, H. & Nurse, P. Fission yeast Fizzy-related protein Srw1p is a G1-specific promoter of mitotic cyclin B degradation. EMBO J. 19, 3968–3977 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Visintin, R. et al. The phosphatase Cdc14 triggers mitotic exit by reversal of Cdk-dependent phosphorylation. Mol. Cell 2, 709–718 (1998).

    CAS  PubMed  Google Scholar 

  81. 81

    Hagting, A. et al. Human securin proteolysis is controlled by the spindle checkpoint and reveals when the APC/C switches from activation by Cdc20 to Cdh1. J. Cell Biol. 157, 1125–1137 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Prinz, S., Hwang, E. S., Visintin, R. & Amon, A. The regulation of Cdc20 proteolysis reveals a role for APC components Cdc23 and Cdc27 during S phase and early mitosis. Curr. Biol. 8, 750–760 (1998).

    CAS  PubMed  Google Scholar 

  83. 83

    Shirayama, M., Zachariae, W., Ciosk, R. & Nasmyth, K. The Polo-like kinase Cdc5p and the WD-repeat protein Cdc20p/Fizzy are regulators and substrates of the anaphase promoting complex in Saccharomyces cerevisiae. EMBO J. 17, 1336–1349 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Sorensen, C. S. et al. Nonperiodic activity of the human anaphase-promoting complex-Cdh1 ubiquitin ligase results in continuous DNA synthesis uncoupled from mitosis. Mol. Cell Biol. 20, 7613–7623 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Huang, J. N., Park, I., Ellingson, E., Littlepage, L. E. & Pellman, D. Activity of the APCCdh1 form of the anaphase-promoting complex persists until S phase and prevents the premature expression of Cdc20p. J. Cell Biol. 154, 85–94 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Knoblich, J. A. et al. Cyclin E controls S phase progression and its down-regulation during Drosophila embryogenesis is required for the arrest of cell proliferation. Cell 77, 107–120 (1994).

    CAS  PubMed  Google Scholar 

  87. 87

    Dong, X. et al. Control of G1 in the developing Drosophila eye: Rca1 regulates Cyclin A. Genes Dev. 11, 94–105 (1997).

    CAS  PubMed  Google Scholar 

  88. 88

    Grosskortenhaus, R. & Sprenger, F. Rca1 inhibits APC–Cdh1Fzr and is required to prevent cyclin degradation in G2. Dev. Cell 2, 29–40 (2002).

    CAS  PubMed  Google Scholar 

  89. 89

    Lukas, C. et al. Accumulation of cyclin B1 requires E2F and cyclin-A-dependent rearrangement of the anaphase-promoting complex. Nature 401, 815–818 (1999).

    CAS  PubMed  Google Scholar 

  90. 90

    Hsu, J. Y., Reimann, J. D., Sorensen, C. S., Lukas, J. & Jackson, P. K. E2F-dependent accumulation of hEmi1 regulates S phase entry by inhibiting APCCdh1. Nature Cell Biol. 4, 358–366 (2002).

    CAS  PubMed  Google Scholar 

  91. 91

    Reimann, J. D., Gardner, B. E., Margottin-Goguet, F. & Jackson, P. K. Emi1 regulates the anaphase-promoting complex by a different mechanism than Mad2 proteins. Genes Dev. 15, 3278–3285 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92

    Rape, M. & Kirschner, M. W. Autonomous regulation of the anaphase-promoting complex couples mitosis to S-phase entry. Nature 432, 588–595 (2004).

    CAS  PubMed  Google Scholar 

  93. 93

    Yamanaka, A. et al. Cell cycle-dependent expression of mammalian E2-C regulated by the anaphase-promoting complex/cyclosome. Mol. Biol. Cell 11, 2821–2831 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Benmaamar, R. & Pagano, M. Involvement of the SCF complex in the control of Cdh1 degradation in S-phase. Cell Cycle 4, 1230–1232 (2005).

    CAS  PubMed  Google Scholar 

  95. 95

    den Elzen, N. & Pines, J. Cyclin A is destroyed in prometaphase and can delay chromosome alignment and anaphase. J. Cell Biol. 153, 121–136 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Geley, S. et al. Anaphase-promoting complex/cyclosome-dependent proteolysis of human cyclin A starts at the beginning of mitosis and is not subject to the spindle assembly checkpoint. J. Cell Biol. 153, 137–148 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    Hames, R. S., Wattam, S. L., Yamano, H., Bacchieri, R. & Fry, A. M. APC/C-mediated destruction of the centrosomal kinase Nek2A occurs in early mitosis and depends upon a cyclin A-type D-box. EMBO J. 20, 7117–7127 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98

    Rieder, C. L., Schultz, A., Cole, R. & Sluder, G. Anaphase onset in vertebrate somatic cells is controlled by a checkpoint that monitors sister kinetochore attachment to the spindle. J. Cell Biol. 127, 1301–1310 (1994).

    CAS  PubMed  Google Scholar 

  99. 99

    Rieder, C. L., Cole, R. W., Khodjakov, A. & Sluder, G. The checkpoint delaying anaphase in response to chromosome monoorientation is mediated by an inhibitory signal produced by unattached kinetochores. J. Cell Biol. 130, 941–948 (1995).

    CAS  PubMed  Google Scholar 

  100. 100

    Musacchio, A. & Hardwick, K. G. The spindle checkpoint: structural insights into dynamic signalling. Nature Rev. Mol. Cell Biol. 3, 731–741 (2002).

    CAS  Google Scholar 

  101. 101

    Li, Y., Gorbea, C., Mahaffey, D., Rechsteiner, M. & Benezra, R. MAD2 associates with the cyclosome/anaphase-promoting complex and inhibits its activity. Proc. Natl Acad. Sci. USA 94, 12431–12436 (1997).

    CAS  PubMed  Google Scholar 

  102. 102

    Fang, G., Yu, H. & Kirschner, M. W. The checkpoint protein MAD2 and the mitotic regulator CDC20 form a ternary complex with the anaphase-promoting complex to control anaphase initiation. Genes Dev. 12, 1871–1883 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103

    Hwang, L. H. et al. Budding yeast Cdc20: a target of the spindle checkpoint. Science 279, 1041–1044 (1998).

    CAS  PubMed  Google Scholar 

  104. 104

    Kim, S. H., Lin, D. P., Matsumoto, S., Kitazono, A. & Matsumoto, T. Fission yeast Slp1: an effector of the Mad2-dependent spindle checkpoint. Science 279, 1045–1047 (1998).

    CAS  PubMed  Google Scholar 

  105. 105

    Sudakin, V., Chan, G. K. & Yen, T. J. Checkpoint inhibition of the APC/C in HeLa cells is mediated by a complex of BUBR1, BUB3, CDC20, and MAD2. J. Cell Biol. 154, 925–936 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106

    Tang, Z., Bharadwaj, R., Li, B. & Yu, H. Mad2-independent inhibition of APCCdc20 by the mitotic checkpoint protein BubR1. Dev. Cell 1, 227–237 (2001).

    CAS  PubMed  Google Scholar 

  107. 107

    Fang, G. Checkpoint protein BubR1 acts synergistically with Mad2 to inhibit anaphase-promoting complex. Mol. Biol. Cell 13, 755–766 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Sironi, L. et al. Mad2 binding to Mad1 and Cdc20, rather than oligomerization, is required for the spindle checkpoint. EMBO J. 20, 6371–6382 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109

    Luo, X., Tang, Z., Rizo, J. & Yu, H. The Mad2 spindle checkpoint protein undergoes similar major conformational changes upon binding to either Mad1 or Cdc20. Mol. Cell 9, 59–71 (2002).

    PubMed  Google Scholar 

  110. 110

    Sironi, L. et al. Crystal structure of the tetrameric Mad1–Mad2 core complex: implications of a 'safety belt' binding mechanism for the spindle checkpoint. EMBO J. 21, 2496–2506 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111

    Shah, J. V. et al. Dynamics of centromere and kinetochore proteins; implications for checkpoint signaling and silencing. Curr. Biol. 14, 942–952 (2004).

    CAS  PubMed  Google Scholar 

  112. 112

    De Antoni, A. et al. The Mad1–Mad2 complex as a template for Mad2 activation in the spindle assembly checkpoint. Curr. Biol. 15, 214–225 (2005). Proposes an elegant prion-like model for the activation of Mad2 that has the capability to explain previously mysterious observations about the spindle-assembly checkpoint.

    CAS  PubMed  Google Scholar 

  113. 113

    Fraschini, R. et al. Bub3 interaction with Mad2, Mad3 and Cdc20 is mediated by WD40 repeats and does not require intact kinetochores. EMBO J. 20, 6648–6659 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114

    Kallio, M., Weinstein, J., Daum, J. R., Burke, D. J. & Gorbsky, G. J. Mammalian p55CDC mediates association of the spindle checkpoint protein Mad2 with the cyclosome/anaphase-promoting complex, and is involved in regulating anaphase onset and late mitotic events. J. Cell Biol. 141, 1393–1406 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115

    Wassmann, K. & Benezra, R. Mad2 transiently associates with an APC–p55Cdc complex during mitosis. Proc. Natl Acad. Sci. USA 95, 11193–11198 (1998).

    CAS  PubMed  Google Scholar 

  116. 116

    Chan, G. K., Jablonski, S. A., Sudakin, V., Hittle, J. C. & Yen, T. J. Human BUBR1 is a mitotic checkpoint kinase that monitors CENP-E functions at kinetochores and binds the cyclosome/APC. J. Cell Biol. 146, 941–954 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117

    Morrow, C. J. et al. Bub1 and Aurora B cooperate to maintain BubR1-mediated inhibition of APC/CCdc20. J. Cell Sci. 118, 3639–3652 (2005).

    CAS  Google Scholar 

  118. 118

    Reimann, J. D. et al. Emi1 is a mitotic regulator that interacts with Cdc20 and inhibits the anaphase promoting complex. Cell 105, 645–655 (2001).

    CAS  PubMed  Google Scholar 

  119. 119

    Hansen, D. V., Loktev, A. V., Ban, K. H. & Jackson, P. K. Plk1 regulates activation of the anaphase promoting complex by phosphorylating and triggering SCFβTrCP-dependent destruction of the APC inhibitor Emi1. Mol. Biol. Cell 15, 5623–5634 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120

    Moshe, Y., Boulaire, J., Pagano, M. & Hershko, A. 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. USA 101, 7937–7942 (2004).

    CAS  PubMed  Google Scholar 

  121. 121

    Guardavaccaro, D. et al. Control of meiotic and mitotic progression by the F box protein β-Trcp1 in vivo. Dev. Cell 4, 799–812 (2003).

    CAS  PubMed  Google Scholar 

  122. 122

    Margottin-Goguet, F. et al. Prophase destruction of Emi1 by the SCFβTrCP/Slimb ubiquitin ligase activates the anaphase promoting complex to allow progression beyond prometaphase. Dev. Cell 4, 813–826 (2003).

    CAS  PubMed  Google Scholar 

  123. 123

    Sumara, I. et al. Roles of Polo-like kinase 1 in the assembly of functional mitotic spindles. Curr. Biol. 14, 1712–1722 (2004).

    CAS  PubMed  Google Scholar 

  124. 124

    van Vugt, M. A. T. M. et al. Polo-like kinase-1 is required for bipolar spindle formation but is dispensable for anaphase promoting complex/Cdc20 activation and initiation of cytokinesis. J. Biol. Chem. 279, 36841–36854 (2004).

    CAS  PubMed  Google Scholar 

  125. 125

    Cooper, K. F., Mallory, M. J., Egeland, D. E. & Strich, R. Ama1p is a meiosis specific regulator of the anaphase promoting complex/cyclosome in yeast. Proc. Natl Acad. Sci. USA 97, 14548–14553 (2000).

    CAS  PubMed  Google Scholar 

  126. 126

    Oelschlaegel, T. et al. The yeast APC/C subunit Mnd2 prevents premature sister chromatid separation triggered by the meiosis-specific APC/C–Ama1. Cell 120, 773–788 (2005). Shows that the meiosis-specific co-activator Ama1 is regulated by surprisingly complex mechanisms in budding yeast.

    CAS  PubMed  Google Scholar 

  127. 127

    Penkner, A. M., Prinz, S., Ferscha, S. & Klein, F. Mnd2, an essential antagonist of the anaphase-promoting complex during meiotic prophase. Cell 120, 789–801 (2005).

    CAS  PubMed  Google Scholar 

  128. 128

    Yoon, H. J. et al. Proteomics analysis identifies new components of the fission and budding yeast anaphase-promoting complexes. Curr. Biol. 12, 2048–2054 (2002).

    CAS  PubMed  Google Scholar 

  129. 129

    Hall, M. C., Torres, M. P., Schroeder, G. K. & Borchers, C. H. Mnd2 and Swm1 are core subunits of the Saccharomyces cerevisiae anaphase-promoting complex. J. Biol. Chem. 278, 16698–16705 (2003).

    CAS  PubMed  Google Scholar 

  130. 130

    Izawa, D., Goto, M., Yamashita, A., Yamano, H. & Yamamoto, M. Fission yeast Mes1p ensures the onset of meiosis II by blocking degradation of cyclin Cdc13p. Nature 434, 529–533 (2005).

    CAS  PubMed  Google Scholar 

  131. 131

    Masui, Y. & Markert, C. Cytoplasmic control of nuclear behaviour during meiotic maturation of frog oocytes. J. Exp. Zool. 177, 129–146 (1971).

    CAS  PubMed  Google Scholar 

  132. 132

    Vorlaufer, E. & Peters, J.-M. Regulation of the cyclin B degradation system by an inhibitor of mitotic proteolysis. Mol. Biol. Cell 9, 1817–1831 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133

    Tunquist, B. J. & Maller, J. L. Under arrest: cytostatic factor (CSF)-mediated metaphase arrest in vertebrate eggs. Genes Dev. 17, 683–710 (2003).

    CAS  PubMed  Google Scholar 

  134. 134

    Schwab, M. S. et al. Bub1 is activated by the protein kinase p90Rsk during Xenopus oocyte maturation. Curr. Biol. 11, 141–150 (2001).

    CAS  PubMed  Google Scholar 

  135. 135

    Tunquist, B. J., Eyers, P. A., Chen, L. G., Lewellyn, A. L. & Maller, J. L. Spindle checkpoint proteins Mad1 and Mad2 are required for cytostatic factor-mediated metaphase arrest. J. Cell Biol. 163, 1231–1242 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136

    Reimann, J. D. & Jackson, P. K. Emi1 is required for cytostatic factor arrest in vertebrate eggs. Nature 416, 850–854 (2002).

    CAS  PubMed  Google Scholar 

  137. 137

    Ohsumi, K., Koyanagi, A., Yamamoto, T. M., Gotoh, T. & Kishimoto, T. Emi1-mediated M-phase arrest in Xenopus eggs is distinct from cytostatic factor arrest. Proc. Natl Acad. Sci. USA 101, 12531–12536 (2004).

    CAS  PubMed  Google Scholar 

  138. 138

    Rauh, N. R., Schmidt, A., Bormann, J., Nigg, E. A. & Mayer, T. U. Calcium triggers exit from meiosis II by targeting the APC/C inhibitor XErp1 for degradation. Nature 437, 1048–1052 (2005). Shows how fertilization of vertebrate eggs inactivates the APC/C inhibitor XErp1 and thereby triggers entry into anaphase II and exit from meiosis.

    CAS  PubMed  Google Scholar 

  139. 139

    Schmidt, A. et al. Xenopus polo-like kinase Plx1 regulates XErp1, a novel inhibitor of APC/C activity. Genes Dev. 19, 502–513 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140

    Tung, J. J. et al. A role for the anaphase-promoting complex inhibitor Emi2/XErp1, a homolog of early mitotic inhibitor 1, in cytostatic factor arrest of Xenopus eggs. Proc. Natl Acad. Sci. USA 102, 4318–4323 (2005).

    CAS  PubMed  Google Scholar 

  141. 141

    Shoji, S. et al. Mammalian Emi2 mediates cytostatic arrest and transduces the signal for meiotic exit via Cdc20. EMBO J. 25, 834–845 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142

    Hansen, D. V., Tung, J. J. & Jackson, P. K. CaMKII and polo-like kinase 1 sequentially phosphorylate the cytostatic factor Emi2/XErp1 to trigger its destruction and meiotic exit. Proc. Natl Acad. Sci. USA 103, 608–613 (2006).

    CAS  PubMed  Google Scholar 

  143. 143

    Kashevsky, H. et al. The anaphase promoting complex/cyclosome is required during development for modified cell cycles. Proc. Natl Acad. Sci. USA 99, 11217–11222 (2002).

    CAS  PubMed  Google Scholar 

  144. 144

    King, R. W., Deshaies, R. J., Peters, J. M. & Kirschner, M. W. How proteolysis drives the cell cycle. Science 274, 1652–1659 (1996).

    CAS  PubMed  Google Scholar 

  145. 145

    Mailand, N. & Diffley, J. F. CDKs promote DNA replication origin licensing in human cells by protecting Cdc6 from APC/C-dependent proteolysis. Cell 122, 915–926 (2005).

    CAS  PubMed  Google Scholar 

  146. 146

    Littlepage, L. E. & Ruderman, J. V. Identification of a new APC/C recognition domain, the A box, which is required for the Cdh1-dependent destruction of the kinase Aurora-A during mitotic exit. Genes Dev. 16, 2274–2285 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. 147

    Lindon, C. & Pines, J. Ordered proteolysis in anaphase inactivates Plk1 to contribute to proper mitotic exit in human cells. J. Cell Biol. 164, 233–241 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. 148

    Rape, M., Reddy, S. K. & Kirschner, M. W. The processivity of multiubiquitination by the APC determines the order of substrate degradation. Cell 124, 89–103 (2006). Provides an elegant mechanistic explanation for the phenomenon that different substrates of APC/CCdh1 are degraded at different times.

    CAS  PubMed  Google Scholar 

  149. 149

    Acquaviva, C., Herzog, F., Kraft, C. & Pines, J. The anaphase promoting complex/cyclosome is recruited to centromeres by the spindle assembly checkpoint. Nature Cell Biol. 6, 892–898 (2004).

    CAS  PubMed  Google Scholar 

  150. 150

    Tugendreich, S., Tomkiel, J., Earnshaw, W. & Hieter, P. CDC27Hs colocalizes with CDC16Hs to the centrosome and mitotic spindle and is essential for the metaphase to anaphase transition. Cell 81, 261–268 (1995).

    CAS  PubMed  Google Scholar 

  151. 151

    Huang, J. & Raff, J. W. The disappearance of cyclin B at the end of mitosis is regulated spatially in Drosophila cells. EMBO J. 18, 2184–2195 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. 152

    Raff, J. W., Jeffers, K. & Huang, J. Y. The roles of Fzy/Cdc20 and Fzr/Cdh1 in regulating the destruction of cyclin B in space and time. J. Cell Biol. 157, 1139–1149 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. 153

    Wakefield, J. G., Huang, J. Y. & Raff, J. W. Centrosomes have a role in regulating the destruction of cyclin B in early Drosophila embryos. Curr. Biol. 10, 1367–1370 (2000).

    CAS  PubMed  Google Scholar 

  154. 154

    Jaquenoud, M., van Drogen, F. & Peter, M. Cell cycle-dependent nuclear export of Cdh1p may contribute to the inactivation of APC/CCdh1. EMBO J. 21, 6515–6526 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. 155

    Yudkovsky, Y., Shteinberg, M., Listovsky, T., Brandeis, M. & Hershko, A. Phosphorylation of Cdc20/fizzy negatively regulates the mammalian cyclosome/APC in the mitotic checkpoint. Biochem. Biophys. Res. Commun. 271, 299–304 (2000).

    CAS  PubMed  Google Scholar 

  156. 156

    D'Angiolella, V., Mari, C., Nocera, D., Rametti, L. & Grieco, D. The spindle checkpoint requires cyclin-dependent kinase activity. Genes Dev. 17, 2520–2525 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. 157

    Pfleger, C. M., Salic, A., Lee, E. & Kirschner, M. W. Inhibition of Cdh1–APC by the MAD2-related protein MAD2L2: a novel mechanism for regulating Cdh1. Genes Dev. 15, 1759–1764 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. 158

    Chen, J. & Fang, G. MAD2B is an inhibitor of the anaphase-promoting complex. Genes Dev. 15, 1765–1770 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. 159

    Tang, Z., Shu, H., Oncel, D., Chen, S. & Yu, H. Phosphorylation of Cdc20 by Bub1 provides a catalytic mechanism for APC/C inhibition by the spindle checkpoint. Mol. Cell 16, 387–397 (2004).

    CAS  PubMed  Google Scholar 

  160. 160

    Chung, E. & Chen, R. H. Phosphorylation of Cdc20 is required for its inhibition by the spindle checkpoint. Nature Cell Biol. 5, 748–753 (2003).

    CAS  PubMed  Google Scholar 

  161. 161

    Song, M. S. et al. The tumour suppressor RASSF1A regulates mitosis by inhibiting the APC–Cdc20 complex. Nature Cell Biol. 6, 129–137 (2004).

    CAS  PubMed  Google Scholar 

  162. 162

    Casaletto, J. B. et al. Inhibition of the anaphase-promoting complex by the Xnf7 ubiquitin ligase. J. Cell Biol. 169, 61–71 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. 163

    Jeganathan, K. B., Malureanu, L. & van Deursen, J. M. The Rae1–Nup98 complex prevents aneuploidy by inhibiting securin degradation. Nature 438, 1036–1039 (2005).

    CAS  PubMed  Google Scholar 

  164. 164

    Teodoro, J. G., Heilman, D. W., Parker, A. E. & Green, M. R. The viral protein Apoptin associates with the anaphase-promoting complex to induce G2/M arrest and apoptosis in the absence of p53. Genes Dev. 18, 1952–1957 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. 165

    Wiebusch, L., Bach, M., Uecker, R. & Hagemeier, C. Human cytomegalovirus inactivates the G0/G1-APC/C ubiquitin ligase by Cdh1 dissociation. Cell Cycle 4, 1435–1439 (2005).

    CAS  PubMed  Google Scholar 

  166. 166

    Kornitzer, D., Sharf, R. & Kleinberger, T. Adenovirus E4orf4 protein induces PP2A-dependent growth arrest in Saccharomyces cerevisiae and interacts with the anaphase-promoting complex/cyclosome. J. Cell Biol. 154, 331–344 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. 167

    Zachariae, W., Shin, T. H., Galova, M., Obermaier, B. & Nasmyth, K. Identification of subunits of the anaphase-promoting complex Saccharomyces cerevisiae. Science 274, 1201–1204 (1996).

    CAS  PubMed  Google Scholar 

Download references


I am grateful to A. Musacchio and members of my group for helpful discussions and to H. Stark and D. Barford for providing images. Research in my laboratory is supported by Boehringer Ingelheim, the European Molecular Biology Organization, the 6th Framework Programme of the European Union via the Integrated Project MitoCheck, and the European Science Foundation and the Austrian Science Fund via the EuroDYNA Programme.

Author information



Ethics declarations

Competing interests

The author declares no competing financial interests.

Supplementary information

Supplementary information

Supplementary table 1 (PDF 110 kb)

Related links

Related links


Jan-Michael Peters' homepage


Ubiquitin ligase (E3)

The third enzyme in a series — the first two are designated ubiquitin-activating (E1) and ubiquitin-conjugating (E2) — that is responsible for the ubiquitylation of target proteins. E3 enzymes provide platforms for binding E2 enzymes and specific substrates, thereby coordinating the ubiquitylation of selected substrates.

Polyubiquitin chains

Protein assemblies that are composed of several copies of the small protein ubiquitin. The ubiquitin residues are covalently attached to each other through isopeptide bonds.

26S proteasome

A large multisubunit protease complex that selectively degrades multi-ubiquitylated proteins. It contains a 20S particle that carries the catalytic activity and two regulatory 19S particles.

Cyclin-dependent kinase

(Cdk). A protein kinase that has activity that depends on an association with a cyclin subunit. Cdks are essential for DNA replication and entry into mitosis.

Ubiquitin-activating (E1) enzyme

An enzyme that activates the C-terminal glycine residue of the small protein ubiquitin, allowing it to form a high-energy thioester bond to a specific cysteine residue of the E1. E1 then transfers this activated form of ubiquitin onto ubiquitin-conjugating (E2) enzymes.

Ubiquitin-conjugating (E2) enzyme

An enzyme that forms a thioester bond with a ubiquitin residue, which is transferred to the E2 enzyme from ubiquitin-activating (E1) enzyme. E2 uses the high energy from the thioester bond to generate an isopeptide bond between the ubiquitin residue and a lysine residue on a substrate protein.


A multisubunit ubiquitin ligase complex that is composed of two scaffolding subunits (cullin and Skp1), a RING-finger subunit that binds ubiquitin-conjugating (E2) enzymes and one of many F-box subunits that recruit substrates.


A sequence element (consensus DRF/YIPXR) that was first found in the N-terminal region of Cdc20. It is conserved in all known APC/C co-activators.


A sequence element (consensus IR) at the extreme C terminus of APC/C co-activators and the APC/C subunit Doc1.

WD40 domain

A propeller-shaped protein domain that is composed of sequence repeats that are 40-amino-acid residues long and contain tryptophan (W) and aspartate (D) residues in conserved positions. In most cases, seven WD40 repeats fold into a seven-bladed propeller structure.


(Destruction-box). A sequence element (consensus RXXLXXXN) that was first discovered in the N terminus of mitotic cyclins that is required for their destruction. D-boxes can be recognized by APC/CCdc20 and by APC/CCdh1.


A sequence element (consensus KEN) that is present in many APC/C substrates. KEN-boxes are preferentially, but not exclusively, recognized by APC/CCdh1.


A member of the cullin family of proteins. All cullins are subunits of SCF ubiquitin ligases or APC/C, and they bind to a RING-finger subunit via a conserved cullin domain.

RING finger

A small protein domain that binds two atoms of zinc (consensus CXXCX(9–39)CX(1–3)HX(2–3)C/HXXCX(4–48)CXXC). Many RING-finger domains interact with ubiquitin-conjugating (E2) enzymes and have ubiquitin ligase (E3) activity.

TPR domain

(Tetratrico peptide repeat domain). A 34-amino-acid sequence repeat, clusters of which fold into a helical structure and mediate protein–protein interactions.


A surveillance mechanism that delays progression through the cell cycle if processes such as DNA replication and spindle assembly have not been completed.


A large proteinacous structure that assembles on centromeric DNA, binds the plus ends of microtubules and thereby connects chromosomes with spindle poles.


The physiological state of cells that are not in the cell cycle.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Peters, J. The anaphase promoting complex/cyclosome: a machine designed to destroy. Nat Rev Mol Cell Biol 7, 644–656 (2006).

Download citation

Further reading


Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing