What Are The Specific Mechanistic Differences In The Regulation Of The Spindle Assembly Checkpoint (SAC) Between Cells Undergoing Mitotic Slippage Versus Those Experiencing A Prolonged G2/M Arrest In Response To DNA Damage, And How Do These Differences Impact The Fidelity Of Chromosome Segregation In Cells With Compromised DNA Integrity?

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The regulation of the spindle assembly checkpoint (SAC) differs significantly between mitotic slippage and prolonged G2/M arrest, impacting chromosome segregation fidelity as follows:

Mechanistic Differences:

  1. Mitotic Slippage:

    • SAC Inactivation: Mitotic slippage occurs when the SAC is inactivated or fails. This allows the cell to exit mitosis without ensuring all chromosomes are properly attached to the spindle apparatus. Defects in SAC components, such as Bub1 or Mad1, or the presence of inhibitors, can lead to this failure.
    • Consequence: The cell bypasses the SAC, leading to mitotic exit despite improper chromosome attachment, which can result in tetraploidy or aneuploidy.

  2. Prolonged G2/M Arrest:

    • DNA Damage Checkpoint Activation: In response to DNA damage, the G2/M checkpoint is activated, preventing the cell from entering mitosis. This checkpoint is regulated by proteins like p53 and Wee1, which inhibit CDK1 activity necessary for mitotic entry.
    • SAC Engagement: If the cell bypasses the G2/M checkpoint and enters mitosis with DNA damage, the SAC may still activate if there are issues like misattached kinetochores, leading to a prolonged mitotic arrest. However, if the SAC is compromised, mitotic slippage can occur.

Impact on Chromosome Segregation Fidelity:

  • Mitotic Slippage: Results in high chances of chromosome missegregation due to the failure of the SAC to ensure proper spindle attachment, leading to aneuploidy or tetraploidy.
  • G2/M Arrest: Aims to preserve segregation fidelity by delaying mitosis until DNA damage is repaired. Effective G2/M arrest prevents mitotic entry with damaged DNA, avoiding segregation errors. However, if both G2/M and SAC checkpoints fail, significant missegregation can occur.

Summary:

Mitotic slippage involves SAC failure, allowing mitotic exit without proper chromosome attachment, while G2/M arrest involves DNA damage checkpoints preventing mitotic entry. The fidelity of chromosome segregation is compromised in mitotic slippage due to SAC failure, whereas effective G2/M arrest maintains fidelity by delaying mitosis for DNA repair.