Figure 17–16 An overview of the cell-cycle control system. The core of the cell-cycle control system consists of a series of cyclin–Cdk complexes (yellow). The activity of each complex is also influenced by various inhibitory mechanisms, which provide information about the extracellular environment, cell damage, and incomplete cell-cycle events (top). These inhibitory mechanisms are not present in all cell types; many are missing in early embryonic cell cycles, for example.
The cell-cycle control system triggers the events of the cell cycle and ensures that they are properly timed and coordinated with each other. The control system responds to various intracellular and extracellular signals and arrests the cycle when the cell either fails to complete an essential cell-cycle process or encounters unfavorable environmental or intracellular conditions.
Central components of the control system are the cyclin-dependent protein kinases (Cdks), which depend on cyclin subunits for their activity. Oscillations in the activities of different cyclin–Cdk complexes control various cell-cycle events. Thus, activation of S-phase cyclin–Cdk complexes (S-Cdk) initiates S phase, whereas activation of M-phase cyclin–Cdk complexes (M-Cdk) triggers mitosis. The mechanisms that control the activities of cyclin–Cdk complexes include phosphorylation of the Cdk subunit, binding of Cdk inhibitor proteins (CKIs), proteolysis of cyclins, and changes in the transcription of genes encoding Cdk regulators. The cell-cycle control system also depends crucially on two additional enzyme complexes, the APC/C and SCF ubiquitin ligases, which catalyze the ubiquitylation and consequent destruction of specific regulatory proteins that control critical events in the cycle.
The linear chromosomes of eukaryotic cells are vast and dynamic assemblies of DNA and protein, and their duplication is a complex process that takes up a major fraction of the cell cycle. Not only must the long DNA molecule of each chromosome be duplicated accurately—a remarkable feat in itself—but the protein packaging surrounding each region of that DNA must also be reproduced, ensuring that the daughter cells inherit all features of chromosome structure.
The central event of chromosome duplication—DNA replication—poses two problems for the cell. First, replication must occur with extreme accuracy to minimize the risk of mutations in the next cell generation. Second, every nucleotide in the genome must be copied once, and only once, to prevent the damaging effects of gene amplification. In Chapter 5, we discuss the sophisticated protein machinery that performs DNA replication with astonishing speed and accuracy. In this section, we consider the elegant mechanisms by which the cell-cycle control system initiates the replication process and, at the same time, prevents it from happening more than once per cycle.
DNA replication begins at origins of replication, which are scattered at numerous locations in every chromosome. During S phase, DNA replication is initiated at these origins when a DNA helicase unwinds the double helix and DNA replication enzymes are loaded onto the two single-stranded templates. This leads to the elongation phase of replication, when the replication machinery moves outward from the origin at two replication forks (discussed in Chapter 5).
To ensure that chromosome duplication occurs only once per cell cycle, the initiation phase of DNA replication is divided into two distinct steps that occur at different times in the cell cycle (Figure 17–17). The first step occurs in late mitosis and early G1, when a pair of inactive DNA helicases is loaded onto the replication origin, forming a large complex called the prereplicative complex or preRC. This step is sometimes called licensing of replication origins because initiation of DNA synthesis is permitted only at origins containing a preRC. The second step occurs in S phase, when the DNA helicases are activated, resulting in DNA unwinding and the initiation of DNA synthesis. Once a replication origin has been fired in this way, the two helicases move out from the origin with the replication forks, and that origin cannot be reused until a new preRC is assembled there at the end of mitosis. As a result, origins can be activated only once per cell cycle.