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Chapter 11
Cell Cycle Regulation
By
Srinivas Venkatram, Kathleen L. Gould, & Susan
L. Forsburg
11.1 Introduction
• A cell contains all the information necessary
for making a copy of itself during a cell
division cycle.
• The eukaryotic cell division cycle (cell cycle)
is composed of an ordered set of events.
– It results in the generation of two copies of a
preexisting cell.
11.1
Introduction
• The cell cycle is partitioned into distinct
phases during which different events
take place.
• Two important phases of the cell cycle
are:
– Replication of a cell’s chromosomes
– Chromosome segregation
11.2 There are several experimental
systems used in cell cycle analyses
• Studies in a wide variety of organisms
have contributed to our knowledge of
cell cycle regulation.
– Each has advantages and disadvantages.
• Genetic analyses of the cell cycle in
yeasts identified conserved cell cycle
regulators.
11.2 There are several experimental systems used in cell cycle
analyses
• Biochemical analyses of protein
complexes from multicellular organisms
complemented the genetic studies of
single-celled organisms.
• Synchronized populations of cells are
important for analyzing cell cycle
events.
11.3 The cell cycle requires coordination
between events
• Checkpoints act to:
– ensure error-free completion of DNA
replication before entry into mitosis
– maintain the temporal coordination of S
and M phases
11.4 The cell cycle as a cycle of CDK
activities
• CDKs:
– are the master regulators of the cell cycle
– are active only when complexed with cyclin
proteins
11.4 The cell cycle as a cycle of CDK
activities
• Cyclins derive their name from the
periodic oscillation of their protein levels
during the cell cycle.
• A CDK can be partnered with different
cyclins during different phases of the
cell cycle.
11.5 CDK-cyclin complexes are regulated
in several ways
• CDK-cyclin complexes are regulated by:
– phosphorylation
– inhibitory proteins
– proteolysis
– subcellular localization
11.6 Cells may exit from and reenter the
cell cycle
• Cells may be maintained in a
nondividing state called quiescence, or
G0.
• Quiescent cells may be stimulated to
return to the cell cycle by environmental
cues.
11.6 Cells may exit from and reenter the cell
cycle
• Cells reenter the cell cycle primarily at
G1.
• Cells may also permanently leave the
cell cycle by differentiating into a
specialized cell type.
• Some cells are programmed to selfdestruct by apoptosis.
11.7 Entry into cell cycle is tightly
regulated
• Cell divisions are not continuous.
– They are controlled by:
• external stimuli
• nutrient availability
• Cells detect the presence of chemical
signals in their environment.
11.7 Entry into cell cycle is tightly
regulated
• Extracellular signals can elicit an
intracellular biochemical response that
results in either:
– entry into the cell cycle or
– cell cycle arrest in a G1/G0 phase
11.8 DNA replication requires the ordered
assembly of protein complexes
• Replication occurs after cells progress
through the restriction point or START.
• Replication:
– is regulated in a stepwise fashion
– is coordinated with the completion of
mitosis
11.8 DNA replication requires the ordered assembly of protein
complexes
• Replication occurs at origins that may be
defined by:
– Sequence or
– Position or
– Spacing mechanisms
• Initiation occurs only at origins that are
licensed to replicate.
• Once fired, origins cannot be reused until the
next cell cycle.
11.9 Mitosis is orchestrated by several
protein kinases
• The transition from G2 to M is a major
control point in many eukaryotic cells.
• Activation of several protein kinases is
associated with the G2-M transition.
11.10 Many morphological changes occur
during mitosis
• The nuclear and cytoskeletal architectures
change dramatically for mitosis.
• Mitotic kinases are required for the proper
execution of mitotic events such as:
–
–
–
–
nuclear envelope breakdown
chromosome condensation and segregation
spindle assembly
cytokinesis
11.11 Mitotic chromosome condensation
and segregation depend on condensin
and cohesin
• In preparation for separation,
chromosomes:
– condense
– move to the center of the mitotic spindle
• Chromosomes become attached to
microtubules emanating from opposite
poles of the spindle through specialized
regions called kinetochores.
11.11 Mitotic chromosome condensation and segregation depend on condensin
and cohesin
• Cohesion that binds sister chromatids
together is released.
– This enables their separation.
• Independent sister chromatids are
further separated in space before
cytokinesis.
11.12 Exit from mitosis requires more
than cyclin proteolysis
• Exit from mitosis requires inactivation of
Cdk1.
• Mitotic exit also involves the reversal of
Cdk1 phosphorylation.
11.12 Exit from mitosis requires more than cyclin
proteolysis
• Inactivation of Cdk1 and reversal of
Cdk1 phosphorylation are coordinated
with:
– disassembly of the mitotic spindle
– cytokinesis
11.13 Checkpoint controls coordinate
different cell cycle events
• Cell cycle events are coordinated with
one another.
• The coordination of cell cycle events is
achieved by the action of specific
biochemical pathways called
checkpoints.
– Checkpoints delay cell cycle progression if
a previous cell cycle event has not been
completed.
11.13 Checkpoint controls coordinate different cell cycle
events
• Checkpoints may be essential only
when cells are stressed or damaged.
– They may also act during a normal cell
cycle to ensure proper coordination of
events.
11.14 DNA replication and DNA damage
checkpoints monitor defects in DNA
metabolism
• Incomplete and/or defective DNA
replication activates a cell cycle
checkpoint.
11.14 DNA replication and DNA damage checkpoints monitor defects in DNA
metabolism
• Damaged DNA activates a different
checkpoint that shares some
components with the replication
checkpoint.
• The DNA damage checkpoint halts the
cell cycle at different stages depending
on the stage during which the damage
occurred.
11.15 The spindle assembly checkpoint
monitors defects in chromosomemicrotubule attachment
• The mitotic spindle attaches to
individual kinetochores of chromosomes
during mitosis.
• Proper attachment of microtubules to
kinetochores is a prerequisite for
chromosome segregation.
11.15 The spindle assembly checkpoint monitors defects in chromosome-microtubule
attachment
• Defects in spindle-MT attachment are
sensed by the “spindle assembly
checkpoint.”
• This checkpoint subsequently halts the
metaphase-anaphase transition to
prevent errors in sister chromatid
separation.
11.16 Cell cycle deregulation can lead to
cancer
• Proto-oncogenes encode proteins that drive
cells into the cell cycle.
• Tumor suppressor genes encode proteins
that restrain cell cycle events.
• Mutations in proto-oncogenes, tumor
suppressor genes, or checkpoint genes may
lead to cancer.