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Finishing mitosis, one step at a time

Nature Reviews Molecular Cell Biology volume 8, pages 894–903 (2007)Cite this article

Key Points

  • The completion of mitosis is governed by the dephosphorylation of cyclin-dependent kinase (Cdk) substrates and by the ubiquitination of anaphase-promoting complex (APC) substrates. The order in which these substrates are modified helps to establish the order of late mitotic events.

  • The order of Cdk-substrate dephosphorylation depends in part on the timing of Cdk inactivation, which is determined primarily by the order of destruction of different cyclin types.

  • Cdk-substrate dephosphorylation also depends on phosphatases, of which the best-known example is Cdc14 of budding yeast. The two-step Cdc14 activation process helps to determine the sequence of Cdk-substrate dephosphorylation.

  • APC activity and substrate specificity depend on the interaction of APC with the activating subunits Cdc20 and Cdh1. The sequential activation of APC by these subunits — Cdc20 first, followed by Cdh1 — determines the order of APC-substrate modification.

  • The spindle-assembly checkpoint contributes to APC-substrate ordering by delaying the ubiquitination of some substrates until chromosomes are properly attached to the mitotic spindle.

  • APC-substrate ordering also depends on the intrinsic differences in the activity of the APC towards different substrates.

Abstract

The final stages of mitosis begin in anaphase, when the mitotic spindle segregates the duplicated chromosomes. Mitotic exit is then completed by disassembly of the spindle and packaging of chromosomes into daughter nuclei. The successful completion of mitosis requires that these events occur in a strict order. Two main mechanisms govern progression through late mitosis: dephosphorylation of cyclin-dependent kinase (Cdk) substrates and destruction of the substrates of the anaphase-promoting complex (APC). Here, we discuss the hypothesis that the order of late mitotic events depends, at least in part, on the order in which different Cdk and APC substrates are dephosphorylated or destroyed, respectively.

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Figure 1: Control of late mitotic events.
Figure 2: The order of mitotic cyclin destruction.
Figure 3: Control of Cdc14 activation by separase and the MEN.
Figure 4: The order of Cdk substrate dephosphorylation during mitosis.
Figure 5: Three windows of APC-dependent destruction in human cells.

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  1. Departments of Physiology and Biochemistry & Biophysics, University of California, 600 16th Street, San Francisco, 94158-2517, California, USA

    Matt Sullivan & David O. Morgan

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Glossary

Hydrophobic patch

A short stretch of amino acids on the surface of some cyclins near the Cdk active site. It interacts with RXL motifs on cyclin-specific Cdk substrates or inhibitors.

RXL motif

A degenerate sequence motif on some Cdk substrates and inhibitors. It interacts with the hydrophobic patch region of specific cyclins.

Kinetochore

A large protein structure that assembles on the chromosome and mediates the attachment of the chromosome to microtubules of the mitotic spindle.

Spindle midzone

The region at the equator of the mitotic spindle where interpolar microtubules overlap. During anaphase, this region helps to organize proteins that govern anaphase spindle behaviour and that control the initiation of cytokinesis.

26S proteasome

A large protease complex that binds polyubiquitinated proteins and degrades them.

Destruction box

(D-box). A degenerate sequence motif (RXXLXXXXN) that is in most APC targets. The D-box mediates an interaction with APC activator subunits and is required for target destruction.

KEN box

A degenerate sequence motif (KENXXXN) that is in some APC targets. The KEN box mediates an interaction with the APC activator Cdh1.

Polo-like kinase-1

(Plk1). A protein kinase that is activated during early mitosis and that helps to promote certain mitotic events, such as spindle assembly.

Aurora kinases A and B

Related protein kinases that are activated during early mitosis and govern spindle assembly, chromosome attachment to kinetochores and other mitotic processes.

Spindle-assembly checkpoint

A regulatory system that monitors chromosome attachment to the mitotic spindle and delays APC activation until all chromosomes are correctly bi-orientated.

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Sullivan, M., Morgan, D. Finishing mitosis, one step at a time. Nat Rev Mol Cell Biol 8, 894–903 (2007). https://doi.org/10.1038/nrm2276

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