Cell Biology - lecture 10 - Cell Cycle

The Cell Cycle Overview

  • The cell cycle is coordinated and controlled at multiple levels: time, position, environment, and damage.

  • Eukaryotic cell cycle phases include G1, S, G2, and M phases.

  • Cyclin and cyclin-dependent kinase (CDK) heterodimers drive the eukaryotic cell cycle.

  • Prokaryotic cell cycle differs, involving processes such as binary fission.

Purpose of the Cell Cycle

  • Replace lost or damaged cells.

  • Enable growth to adult size in multicellular organisms.

  • Maintain total cell number in adult organisms.

  • Copy the genome and partition equally between daughter cells in unicellular and multicellular organisms.

Prokaryotic Cell Division

  • Prokaryotes divide through binary fission:

    • DNA attaches to cytoplasmic membrane

    • Cell enlarges and DNA duplicates.

    • A septum forms to separate the cells, partitioning DNA into each cell.

  • Cell division results in two daughter cells, each containing a nucleoid.

Coordination of Cell Cycle Pathways

  • Two essential pathways must be coordinated:

    1. Replication of DNA (with partition of copies).

    2. Cytokinesis (cell separation).

  • Rapidly growing bacteria face timing issues: cell division (20 min) takes less time than DNA replication (40 min).

  • Leads to situations where cells may not contain fully replicated DNA due to the close timing of events.

  • During cytokinesis, a protein, FtsZ, is formed on the inner surface of the cytoplasmic division sites where the protein ring contracts

Multifork Replication

  • The mismatch in timing is resolved by initiating DNA replication before the previous round completes (multifork replication).

  • This ensures completion of at least one round of replication before cytokinesis begins.

  • Prokaryotes have circular DNA with one origin of replication but two replication forks.

Eukaryotic Cell Cycle Complexity

  • Eukaryotic cells have multiple linear chromosomes which complicates:

    1. Coordinated replication of all chromosomes.

    2. Segregation during cell division.

    3. Partitioning of organelles into daughter cells.

  • Cells exist within the context of organs and tissues, introducing further complexity.

Common Characteristics of Cell Cycles

  • Despite variations, common features include:

    • Faithful replication of DNA.

    • Accurate segregation of replicated chromosomes.

Cell Cycle Phases

  • G1 Phase (Gap 1):

    • Growth phase; organelles and proteins double, synthesis of enzymes for DNA replication.

  • S Phase (DNA Synthesis):

    • Replication of DNA; at the end, each chromosome consists of two identical sister chromatids.

    • Cohesin ensures that sister chromatids do not drift apart

  • G2 Phase:

    • Preparation for mitosis; ensures completion of S phase before entering mitosis.

  • M Phase (Mitosis):

    • Consists of nuclear division (mitosis) and cytoplasmic division (cytokinesis).

  • Interphase: chromosomes not visible and M phase: chromosomes become visible

Chromosome Management During M Phase

  • At the end of S phase, condensin compacts sister chromatids to ensure they remain together until appropriate separation.

  • Chromosome condensation at the start of M phase makes chromosomes visible.

    • condensin encircles loops of DNA and compresses the sister chromatids to give a compact structure

  • Formation of the mitotic spindle occurs, allowing access to chromosomes for segregation.

    • microtubules that connect to the kinetochore when the nuclear membrane breaks down

  • Chromatids segregated when the kleisin subunit of cohesin is cleaved by protease

Cytokinesis

  • The division of the cytoplasm occurs at the end of the cell cycle:

    • In animal cells: a contractile ring divides from outside inward.

      • contractile ring of actin and myosin II filaments

    • In plants: a new cell wall forms between daughter nuclei, partitioning from inside out.

Variations in Cell Cycle

  • Differences include:

    1. Timing of cycles, e.g., somatic cells vs. early embryonic cycles.

    2. Nuclear envelope dynamics:

      • Unicellular organisms may have closed mitosis; multicellular organisms typically undergo open mitosis.

    3. Asymmetric cell division leading to daughter cells with different fates and contents.

  • unicellular organisms operate a closed mitosis meaning the nuclear envelope is always intact

  • multicellular organisms have an open one since the spindle pole body is outside

  • asymmetrical cells - mother cells segregate cell fate determinants to one side and positions the division plase so one daughter inherits the determinant

  • stem cells: attached niche cells which don’t differentiate but divide

    • one daughter differentiates and one stays connected, remaining a stem cell

Cell Cycle Control Mechanisms

  • Key control features include:

    1. Cell cycle engine:

      • Driven by protein kinases, specifically CDKs and their associated cyclins.

    2. Co-ordination:

      • Ensures that DNA replication precedes mitosis.

    3. Checkpoints:

      • Surveillance mechanisms detect issues before proceeding to the next phase (e.g., DNA damage checkpoints).

    4. Anchorage dependence: cells must be attached to a substratum in order to divide

    5. Density-dependent inhibition: cells stop diving once they contact each other (contact inhibition)

CDK-Cyclin Complexes

  • CDKs are activated by cyclins, which are synthesized and degraded cyclically:

    • Different CDK-cyclin pairs are responsible for different phases of the cycle.

    • Kinase levels remain the same

  • Cyclins dictate target proteins that mediate the specific phase of the cycle.

  • Degradation of cyclins is essential for transitioning out of phases (e.g., degradation of cyclin B for exit from mitosis).

    • proteolysis degrades cyclins

  • mitotic CDK phosphorylates nuclear lamin → depolymerisation of lamin filaments → lamin mesh disintegrates and doesn’t support the nuclear membrane

Consequences of Checkpoint Failure

  • Can lead to human aneuploidies (e.g., Down’s Syndrome) and mutations leading to cancer.

  • Cancer cells often ignore checkpoints and communication signals, resulting in deregulated division.

  • G1 - restriction point (R): growth factor will instruct the cell to divide

  • G2/M: checks if DNA synthesis is complete

  • M (spindle) checkpoint: checks to see if each chromosome is attached to the spindle

    • failure = unequal chromosome segregation

  • G0: stops cycle while damage is being repaired

Summary

  • The eukaryotic cell cycle processes ensure precise replication and segregation of chromosomes.

  • The CDK-cyclin complex is central to cell cycle regulation, with multiple levels of checkpoints guarding against errors and mutations.