Cell Cycle Regulation

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Chapter 11

• Cell Cycle Regulation
• By
• Srinivas Venkatram, Kathleen L. Gould, Susan L.
  Forsburg

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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.

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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 cells chromosomes
• Chromosome segregation

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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.

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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.

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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

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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

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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.

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11.5 CDK-cyclin complexes are regulated in
several ways

• CDK-cyclin complexes are regulated by
• phosphorylation
• inhibitory proteins
• proteolysis
• subcellular localization

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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.

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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 self-destruct by
  apoptosis.

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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.

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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

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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

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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.

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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.

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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

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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.

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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.

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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.

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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

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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.

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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.

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11.14 DNA replication and DNA damage checkpoints
monitor defects in DNA metabolism

• Incomplete and/or defective DNA replication
  activates a cell cycle checkpoint.

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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.

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11.15 The spindle assembly checkpoint monitors
defects in chromosome-microtubule attachment

• The mitotic spindle attaches to individual
  kinetochores of chromosomes during mitosis.
• Proper attachment of microtubules to kinetochores
  is a prerequisite for chromosome segregation.

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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.

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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.