Lecture 23

Cell Cycle and Mitosis

Overview of the Cell Cycle

  • The cell cycle is a series of events that take place in a cell leading to its division and duplication (replication).

  • The cycle is divided into different phases that ensure proper cell division and replication of genetic material.

Phases of the Cell Cycle

  1. G1 Phase

    • The first gap phase in the cell cycle.

    • During this phase, cells synthesize all of the proteins, ribosomes, and other machinery required for cell functionality.

  2. S Phase

    • The synthesis phase where DNA is replicated.

    • At the end of S phase, each replicated chromosome consists of a pair of identical sister chromatids glued together.

  3. G2 Phase

    • A second gap phase where the cell prepares for mitosis.

    • Ensures all DNA is replicated and checks for errors before proceeding to M phase.

  4. M Phase

    • The mitotic phase where the cell divides.

    • Involves two main processes: nuclear division (mitosis) and cytoplasmic division (cytokinesis).

Key Concepts in Cell Division

  • Nuclear Division (Mitosis)

    • Each duplicated chromosome is segregated into a pair of daughter nuclei.

    • Mitosis is essential to ensure that each daughter cell receives an identical set of chromosomes.

  • Cytokinesis

    • The division of the cytoplasm into two daughter cells, completing the cell division process.

Nobel Prize References

  • Noteworthy works on cell division include:

    • Leland H. Hartwell: Suggested that most genes regulating cell division were identified.

    • Paul Nurse: Focused on cyclin-dependent kinases (cdks).

    • Timothy Hunt: Studied cyclins, which are key regulators of the cell cycle.

  • More reading: Hartwell Lecture Paper

Temperature-Sensitive Mutants in Yeast

  • Temperature-sensitive mutants were critical in identifying cell cycle control genes.

  • cdc mutants are unable to proceed through certain stages of cell division, particularly before cytokinesis.

  • Normal cells exhibit variances in size which can be linked to mutations affecting cell cycle progression.

Cell-Cycle Control System

  • The cell-cycle control system in eukaryotes shows remarkable similarity across different organisms, including yeast and humans.

  • Complementation of yeast mutants with human genes demonstrates evolutionary conservation in control mechanisms.

  • Experiments called rescue experiments confirm that human cyclins can restore function in yeast cdk mutants.

Cyclin-Dependent Kinases (Cdks)

  • Cdk metrics depend upon their association with cyclins.

  • When cyclins bind to Cdks, they activate the kinase activity which triggers specific cell-cycle events.

    • Without cyclins, Cdks remain inactive.

  • Cyclins are crucial to modulate Cdk activity, determining when and how the cell cycle progresses.

Cyclins and Their Roles

  • There are three principal classes of cyclins required in eukaryotic cells:

    1. G1/S-Cyclins

    • Activate Cdks at the end of G1 phase, committing the cell to DNA replication.

    1. S-Cyclins

    • Activate Cdks during S phase, crucial for the initiation of DNA replication.

    1. M-Cyclins

    • Promote events crucial for mitosis.

  • A potential fourth type, G1-cyclins, controls the start of G1.

Cyclin-Cdk Complexes

  • Each cyclin-Cdk complex phosphorylates a unique set of substrate proteins, signaling different cell cycle processes.

    • Phosphorylation grants an additional level of regulation over Cdk/cyclin interactions.

Regulation Mechanisms

  • Cohesin

    • Cohesin is a protein complex that maintains sister chromatids together until their separation in anaphase.

  • Anaphase Promoting Complex (APC)

    • Activated during metaphase, promotes degradation of M-cyclin, marking proteins for degradation through polyubiquitination.

Mitosis Stages

  1. Prophase

    • Chromosomes condense; the mitotic spindle assembles outside the nucleus.

  2. Prometaphase

    • Breakdown of the nuclear envelope; microtubules interact with chromosomes at the kinetochore region.

  3. Metaphase

    • Chromosomes align at the spindle center; spindle apparatus formation is crucial for alignment.

    • The mitotic spindle is made of microtubules, orchestrating the movement of chromosomes during division.

  4. Anaphase

    • Microtubules shorten, separating sister chromatids into two individual chromosomes as they move towards opposite poles.

  5. Telophase

    • Chromosomes decondense, and a new nuclear envelope forms around each set of chromosomes as they reach the poles.

Cytokinesis

  • Cytokinesis marks the final separation of the two new cells, using a contractile ring made predominantly of actin and myosin.

  • A cleavage furrow forms as the ring tightens, leading to division.

  • Microtubules remaining from the central spindle reorganize to support the new interphase arrangement following cell division.