Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

974 Chapter 17: The Cell Cycle
Summary
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.
S PHASE
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.
S-Cdk Initiates DNA Replication 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 G 1 , 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.
Figure 17–18 illustrates some of the molecular details underlying the control
of the two steps in the initiation of DNA replication. A key player is a large multiprotein
complex called the origin recognition complex (ORC), which binds to