The Cell: A Molecular Approach

Fourth Edition

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Chapter 16: The Cell Cycle

Chapter Summary

The EUKARYOTIC CELL CYCLE

Phases of the Cell Cycle: Eukaryotic cell cycles are divided into four discrete phases: M, G₁, S, and G₂. M phase consists of mitosis, which is usually followed by cytokinesis. S phase is the period of DNA replication.

Regulation of the Cell Cycle by Cell Growth and Extracellular Signals: Extracellular signals and cell size regulate progression through specific control points in the cell cycle.

Cell Cycle Checkpoints: Checkpoints and feedback controls coordinate the events that take place during different phases of the cell cycle and arrest cell cycle progression if DNA is damaged.

Restricting DNA Replication to Once per Cell Cycle: Once DNA replication has taken place, initiation of a new S phase is prevented until the cell has passed through mitosis.

REGULATORS OF CELL CYCLE PROGRESSION

Protein Kinases and Cell Cycle Regulation: MPF is the key molecule responsible for regulating the G₂ to M transition in all eukaryotes. MPF is a dimer of cyclin B and the Cdk1 protein kinase.

Families of Cyclins and Cyclin-Dependent Kinases: Distinct pairs of cyclins and Cdk1-related protein kinases regulate progression through different stages of the cell cycle. The activity of Cdk's is regulated by association with cyclins, activating and inhibitory phosphorylations, and the binding of Cdk inhibitors.

Growth Factors and the Regulation of G₁ Cdk's: Growth factors stimulate animal cell proliferation by inducing synthesis of the D-type cyclins. Cdk4, 6/cyclin D complexes then act to drive cells through the restriction point in G₁. A key substrate of Cdk4, 6/cyclin D complexes is the tumor suppressor protein Rb, which regulates transcription of genes required for cell cycle progression, including cyclin E. Activation of Cdk2/cyclin E complexes is then responsible for entry into S phase.

DNA Damage Checkpoints: DNA damage or incompletely replicated DNA arrest cell cycle progression in G₁, S, and G₂. Cell cycle arrest is mediated by protein kinases that are activated by DNA damage and inhibit Cdc25 phosphatases, which are required for Cdk activation. In mammalian cells, arrest at the G₁ checkpoint is also mediated by p53, which induces synthesis of the Cdk inhibitor p21.

THE EVENTS OF M PHASE

Stages of Mitosis: Mitosis is conventionally divided into four stages: prophase, metaphase, anaphase, and telophase. The basic events of mitosis include chromosome condensation, formation of the mitotic spindle, nuclear envelope breakdown, and attachment of spindle microtubules to chromosomes at the kinetochore. Sister chromatids then separate and move to opposite poles of the spindle. Finally, nuclei re-form, the chromosomes decondense, and cytokinesis divides the cell in half.

Cdk1/Cyclin B and Progression to Metaphase: M phase is initiated by activation of Cdk1/cyclin B, which phosphorylates other protein kinases, as well as the nuclear lamins and other proteins of the nuclear envelope, condensins, and Golgi matrix proteins. Activation of Cdk1/cyclin B is responsible for chromatin condensation, nuclear envelope breakdown, fragmentation of the Golgi apparatus, and reorganization of microtubules to form the mitotic spindle. The attachment of spindle microtubules to the kinetochores of sister chromatids then leads to their alignment on the metaphase plate.

The Spindle Assembly Checkpoint and Progression to Anaphase: Activation of a ubiquitin ligase called the anaphase-promoting complex leads to degradation of key regulatory proteins at the metaphase to anaphase transition. The activity of the anaphase-promoting complex is inhibited until the cell passes the spindle assembly checkpoint and all chromosomes are properly aligned on the spindle. Ubiquitin-mediated proteo­lysis initiated by the anaphase-promoting complex then leads to the degradation of cohesin, breaking the link between sister chromatids at the onset of anaphase. The anaphase-promoting complex also ubiquitinates cyclin B, leading to inactivation of Cdk1 and exit from mitosis.

Cytokinesis: Inactivation of Cdk1/cyclin B also triggers cytokinesis. In yeast and animal cells, cytokinesis results from contraction of a ring of actin and myosin filaments. In higher plant cells, cytokinesis results from the formation of a new cell wall and plasma membrane inside the cell.

MEIOSIS AND FERTILIZATION

The Process of Meiosis: Meiosis is a specialized cell cycle that gives rise to haploid daughter cells. A single round of DNA synthesis is followed by two sequential cell divisions. During meiosis I, homologous chromosomes first form pairs and then segregate to different daughter cells. Meiosis II then resembles a normal mitosis in which sister chromatids separate.

Regulation of Oocyte Meiosis: Meiosis of vertebrate oocytes is regulated at two unique points in the cell cycle: the diplotene stage of meiosis I and metaphase of meiosis II. Metaphase II arrest results from inhibition of the anaphase-promoting complex by a protein kinase expressed in oocytes.

Fertilization: Fertilization triggers the resumption of oocyte meiosis by Ca²⁺-dependent activation of the anaphase-promoting complex. The fertilized egg then contains two haploid nuclei, which form a new diploid genome and initiate embryonic cell divisions.