The biochemistry of mitosis

Abstract

In this article, we will discuss the biochemistry of mitosis in eukaryotic cells. We will focus on conserved principles that, importantly, are adapted to the biology of the organism. It is vital to bear in mind that the structural requirements for division in a rapidly dividing syncytial Drosophila embryo, for example, are markedly different from those in a unicellular yeast cell. Nevertheless, division in both systems is driven by conserved modules of antagonistic protein kinases and phosphatases, underpinned by ubiquitin-mediated proteolysis, which create molecular switches to drive each stage of division forward. These conserved control modules combine with the self-organizing properties of the subcellular architecture to meet the specific needs of the cell. Our discussion will draw on discoveries in several model systems that have been important in the long history of research on mitosis, and we will try to point out those principles that appear to apply to all cells, compared with those in which the biochemistry has been specifically adapted in a particular organism.

Figure 1.

Mitotic entry network. The core regulatory module is indicated as a green rectangle. Dark gray lines indicate the interactions during a nonperturbed mitotic cell cycle. Yellow lines indicate interaction on DNA damage or stress-activated G₂ checkpoint signaling. Question marks in red circles indicate interactions that are contentious or not proven. Green and red colored text indicates processes that are stimulated and inhibited by cyclin B/Cdk1 during mitosis, respectively. Question marks indicate processes in which the direct involvement of cyclin B/Cdk1 is not clear or not proven. APC, Anaphase-promoting complex; CDK, cyclin-dependent kinase; ER, endoplasmic reticulum; SAC, spindle assembly checkpoint.

Figure 2.

APC/C-mediated proteolysis in mitosis. Time line of progress through mitosis with the times at which some important APC/C substrates are degraded indicated below the line. The spindle checkpoint prevents the degradation of all the indicated APC/C substrates, except cyclin A and Nek2A. The exchange of Cdc20 for Cdh1 in anaphase is required for the degradation of Aurora A, but not for some other substrates, including Plk1 and Cdc20. NEBD, nuclear envelope breakdown.

Figure 3.

Simplified model for how the mitotic checkpoint complex (MCC) may be generated at the kinteochore. The Bub1, Bub3, BubR1, Mad1, and Mad2 SAC proteins bind to unattached kinetochore, depending on Mps1 activity. Bub3/Bub1 and Bub3/BubR1 bind Knl1 after phosphorylation by Mps1. Mad1 binds too tightly to one molecule of Mad2 in its closed conformation (Mad2c). The Mad1–Mad2c complex recruits a molecule of Mad2 in its open conformation (Mad2o), and catalyzes a conformational change to Mad2c to enable it to bind Cdc20. Question marks indicate protein–protein interactions and other aspects of MCC assembly that are still incompletely understood.