Biology Reference
In-Depth Information
unidirectional and irreversible: G1
S
G2
M
basic features of cell physiology. Informal, textbook
explanations should not be accepted uncritically. Because
the cell cycle is fundamentally a sequential process played
out in time and space, the control system must be described
in dynamic terms that provide insight into the general
principles of temporal and spatial regulation and which
account in quantitative detail for the idiosyncrasies of cell
growth and division in particular organisms.
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G1
. Second, the cycle of DNA replication and division
must be coordinated with the synthesis of all other cellular
components (proteins, lipids, organelles, etc.). That is, the
time required to complete the cell division cycle must be
identical to the mass-doubling time of cellular growth
processes. If cell growth and division are not balanced in
this way, then cells will get either larger and larger or
smaller and smaller each generation, and eventually they
will die.
Third, although the cell cycle is a periodic process, it is
not governed by a clock [17] . The time spent in each phase
of the cell cycle is highly variable, because progression
from one phase to the next depends not on time spent in the
current phase but on successful completion of the essential
tasks of this phase. These completion requirements are
enforced by checkpoints [18 e 20] that guard the major
transitions of the cell cycle: G1/S, G2/M, M/A (metaphase-
to-anaphase) and T/G1 (telophase, cell division and return
to G1, collectively known as 'exit from mitosis'). A
checkpoint has three components [21] . Its surveillance
mechanism looks for specific problems (incomplete repli-
cation of DNA, misalignment of chromosomes on the
mitotic spindle, DNA damage). When a problem is detec-
ted, its error correction machinery is put into play (damage
repair, reattachment of microtubules to kinetochores, etc.).
In the meantime, the checkpoint proper blocks progression
to the next stage of the cell cycle until the problem is
resolved. These checkpoints ensure that the genome is
passed down intact from generation to generation. When
the checkpoints are compromised by mutations, daughter
cells may inherit seriously damaged chromosomes (e.g.,
missing large pieces of the genome). Chromosomal
abnormalities may trigger programmed cell death or
malignant transformations of the damaged cell.
Fourth, the molecular mechanism controlling all the
events of the cell cycle must be extremely robust: it must
function perfectly under a wide variety of conditions and
stresses, because mistakes can be lethal to the dividing cell
and ultimately to the organism it supports. In particular, we
must keep in mind that these molecular interactions are
occurring within the small confines of a single cell, and the
numbers of molecules participating in any aspect of the
process may be extremely limiting. For example, in
a haploid yeast cell there is (in general) only one copy of
every gene, only a handful of copies of each specific
mRNA, and only a few hundreds or thousands of molecules
of specific regulatory proteins [22,23] . Basic laws of
statistical physics demand that reactions among such small
numbers of molecules must experience large stochastic
fluctuations [24,25] , yet cell cycle events are flawlessly
orchestrated by the noisy molecular control system.
Any proposed explanation of the molecular basis of
eukaryotic cell cycle controls must be consistent with these
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Molecular Biology of the Cell Cycle
In eukaryotes the basic events of the cell cycle e DNA
synthesis and mitosis e are controlled by a family of
cyclin-dependent protein kinases (CDKs). As their name
implies, these enzymes, in conjunction with a suitable
cyclin partner, phosphorylate protein targets [26,27] and
thereby initiate processes such as DNA replication, nuclear
envelope breakdown, chromosome condensation and
mitotic spindle assembly. Hence the timing of cell cycle
events depends on sequential waves of activation and
inactivation of CDKs. During steady proliferation of most
cell types the catalytic subunits (Cdk1, Cdk2, Cdk4 and
Cdk6) are present in excess, and their activities are
dependent on the availability of specific regulatory subunits
(cyclin A, cyclin B, cyclin D, cyclin E) [28] . The abun-
dance of each type of cyclin is controlled by its turnover (its
rates of synthesis and degradation) ( Figure 14.2 ). Cyclin
synthesis rate is determined by the activity of specific
transcription factors, and cyclin degradation rate is
FIGURE 14.2 Mechanisms for regulating the activity of a CDK:
cyclin heterodimer. The kinase subunit, CDK, is usually present in
constant amount, in excess of cyclin subunits. The concentration of cyclin
subunits is determined by the activities of its transcription factor (TFC) and
its degradation machinery (APC or SCF). Active CDK:cyclin dimers can
be inactivated by binding to a stoichiometric inhibitor (CKI), whose
abundance is determined by the activities of its transcription factor (TFI)
and its degradation machinery (SCF). In addition, the kinase subunit can be
inactivated by phosphorylation (kinase ¼ Wee1) and reactivated by
dephosphorylation (phosphatase ¼ Cdc25). The enzymes (TFC, APC, TFI,
SCF, Wee1 and Cdc25) are all subject to their own regulatory interactions.
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