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Cubism and the cell cycle: the many faces of the APC/C

Nature Reviews Molecular Cell Biology volume 12, pages 427–438 (2011)Cite this article

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A Corrigendum to this article was published on 06 July 2011

This article has been updated

Key Points

  • The APC/C (anaphase-promoting complex, also known as the cyclosome) is a multisubunit ubiquitin ligase that regulates the cell cycle by targeting different substrates for degradation at different time points.

  • The APC/C is essential to impose the correct temporal order on the cell cycle.

  • Recent structural data have begun to reveal how the APC/C recognizes its substrates, and in particular the role of its co-activators, CDC20 and CDC20 homologue 1 (CDH1), in forming a bipartite degron receptor.

  • In early mitosis, the APC/C is regulated by the spindle assembly checkpoint (SAC), which sequesters CDC20 into a protein complex to prevent it from forming the substrate receptor for cyclin B and securin. At this time, cyclin A can still be degraded because it can compete with the SAC proteins to bind CDC20.

  • In G1 phase, the CDH1 co-activator replaces CDC20 and has an essential role in regulating cell fate decisions: mating in yeast and differentiation (in particular, endoreplication) in animal cells.

  • The APC/C must be turned off at the end of G1 phase to allow the S phase cyclins to accumulate and cells to begin DNA replication. This requires phosphorylation by cyclin–CDKs in yeast and the early mitotic inhibitor 1 (EMI1; also known as FBXO5) or RCA1 in animal cells.

Abstract

One does not often look to analytic cubism for insights into the control of the cell cycle, but Pablo Picasso beautifully encapsulated the fundamentals when he said that “every act of creation is, first of all, an act of destruction”. The rapid destruction of specific cell cycle regulators at just the right moment in the cell cycle ensures that daughter cells receive an equal and identical set of chromosomes from their mother and that DNA replication always follows mitosis. Remarkably, one protein complex is responsible for this surgical precision, the APC/C (anaphase-promoting complex, also known as the cyclosome). The APC/C is tightly regulated by its co-activators and by the spindle assembly checkpoint.

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Figure 1: The cell cycle.
Figure 2: The APC/C structure.
Figure 3: The spindle assembly checkpoint and the APC/C.
Figure 4: Waves of APC/C-directed proteolysis during mitosis.
Figure 5: Feedback loops between APC/CCDH1, cyclin A, SKP2 and p27KIP1 in G1 phase.

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Change history

  • 06 July 2011

    On page 435 of this article, there was a mistake in the personal communication. The scientists the author received the information from are R. Wolthuis and W. van Zon. This has been corrected online.

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Acknowledgements

I am grateful to D. Barford, M. Malumbres and R. Wolthuis for communicating unpublished data and to D. Morgan for constructive advice on the manuscript. I am also grateful to my laboratory colleagues for their comments and criticisms. I apologize to all those colleagues in the field whose work I have been unable to cite because of space limitations.

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    Jonathon Pines

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Glossary

DNA replication origins

Sites where replication is initiated during S phase. They are bound by the origin of replication complex.

Cullin

A family of proteins present in multisubunit ubiquitin ligases; they recruit RING fingercontaining proteins to the ligase complex.

RING finger E3 ubiquitin ligase

A class of E3 ligases, the RING finger domain of which is responsible for binding, and potentially activating, the E2 enzyme that carries the ubiquitin moiety.

Kinetochores

Multiprotein complexes that assemble on centromeric DNA and mediate the attachment and movement of chromosomes along the microtubules of the mitotic spindle.

EM single particle 3D reconstruction

Structural analysis in which single macromolecules are imaged using an electron microscope and the structure is derived from averaging the images.

Tetratricopeptide repeats

(TPRs). Structural motifs, found in a wide range of proteins, that are composed of 34 amino acids. TPRs are involved in intra- and inter-molecular interactions.

WD40 repeat

A protein motif that is composed of a 40-amino-acid repeat that forms a blade of the characteristic β-propeller structure.

DOC domain family

A family of proteins containing a motif that was originally identified in the destruction of cyclin B 1 (Doc1) protein in budding yeast.

Processivity

A measure of the number of ubiquitin molecules that can be added to a chain in any one round of substrate binding.

Nuclear envelope breakdown

The point at the end of prophase when the nuclear envelope of many eukaryotic cells disassembles.

Distributive substrates

Ubiquitin ligase substrates that require several rounds of binding to the ligase to be polyubiquitylated.

SCFSKP2 ubiquitin ligase

A multisubunit ubiquitin ligase that contains S phase kinase-associated protein 1 (SKP1; a member of the cullin family), SKP2 (an F-box protein) and a RING fingercontaining protein, RING box1.

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Pines, J. Cubism and the cell cycle: the many faces of the APC/C. Nat Rev Mol Cell Biol 12, 427–438 (2011). https://doi.org/10.1038/nrm3132

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