Chapter 11

Cell Cycle RegulationBy

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.

• 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

11.1 Introduction

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.

• 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.

11.2 There are several experimental systems used in cell cycle analyses

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

• 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.

11.4 The cell cycle as a cycle of CDK activities

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.

• 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.

11.6 Cells may exit from and reenter the cell cycle

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.

• 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

11.7 Entry into cell cycle is tightly regulated

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

• 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.

11.8 DNA replication requires the ordered assembly of protein complexes

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.

• Cohesion that binds sister chromatids together is released.– This enables their separation.

• Independent sister chromatids are further separated in space before cytokinesis.

11.11 Mitotic chromosome condensation and segregation depend on condensin and cohesin

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.

• Inactivation of Cdk1 and reversal of Cdk1 phosphorylation are coordinated with:– disassembly of the mitotic spindle – cytokinesis

11.12 Exit from mitosis requires more than cyclin proteolysis

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.

• 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.

11.13 Checkpoint controls coordinate different cell cycle 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.

• 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.

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

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.

• 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.

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

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.