Cell Cycle Checkpoints

Overview

• Discussion focused on cell cycle checkpoints.
• Three main checkpoints: G1/S transition, G2/M transition, and M phase.

G1/S Transition Checkpoint (Restriction Point)

• Function: Assesses environment for growth factors and conditions optimal for cell division. Monitors internal conditions for DNA damage.
• Importance: Prevents replication blockage and faulty chromosome segregation due to DNA damage.
• Molecular Mechanism:
  • Sensing DNA Damage: Utilizes sensors like ATM and ATR.
  • Activation of Key Proteins:
    • ATM/ATR phosphorylate downstream targets (e.g., Che 2, Che 1).
    • Che 1 inhibits Cdc25, preventing activation of Cyclin D/CDK4 and Cyclin E/CDK2 complexes.
  • Role of p53:
    • Activated p53 (not degraded) due to DNA damage.
    • Functions of p53:
      • Activates p21 (cyclin-dependent kinase inhibitor) to block cell cycle progression from G1 to S phase.
      • If damage is irreparable, the cell undergoes apoptosis to prevent faulty chromosome segregation.

G2/M Checkpoint

• Function: Checks for DNA damage and unreplicated DNA before entering mitosis.
• Molecular Mechanism:
  • Requires Cyclin B/CDK1 activity for transition from G2 to M phase.
  • Sensing DNA Damage: ATM/ATR activate Che 1, which inhibits Cdc25 (phosphatase).
  • Inhibition of Cdc25 prevents activation of Cyclin B/CDK1, blocking entry into M phase.

M Phase Checkpoint

• Function: Ensures proper alignment of chromosomes on spindle fibers before segregation.
• Importance: Prevents unequal segregation of chromosomes, which could lead to detrimental consequences for daughter cells.
• Molecular Mechanism:
  • In metaphase, the Anaphase Promoting Complex (APC) inhibits securin, freeing separase to separate chromosomes.
  • Tension Sensing:
    • Tension sensors (e.g., Mad1, Mad2) detect unequal tension and inhibit APC if sensing issues.
    • Inhibition of APC prevents degradation of securin, halting chromosome separation until tension normalizes.

Summary

• All checkpoints play critical roles in maintaining genetic integrity during cell division.
• Concepts from the video are detailed in "Molecular Biology of the Cell" by Alberts et al.

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