Spindle checkpoint

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Spindle Checkpoint

The spindle checkpoint is a crucial regulatory mechanism that ensures the proper segregation of chromosomes during cell division, specifically during mitosis and meiosis. This checkpoint prevents the onset of anaphase until all chromosomes are correctly attached to the spindle apparatus, thereby ensuring genomic stability and preventing aneuploidy.

Overview

The spindle checkpoint is a safeguard that monitors the attachment of chromosomes to the spindle microtubules via kinetochores. It ensures that each daughter cell receives the correct number of chromosomes. The checkpoint operates by inhibiting the anaphase-promoting complex/cyclosome (APC/C) until all chromosomes are properly aligned and attached.

Mechanism

The spindle checkpoint involves several key proteins and complexes:

• Kinetochores: These are protein structures on the chromosome where spindle fibers attach. They play a critical role in sensing attachment and tension.

• Mitotic Checkpoint Complex (MCC): This complex includes proteins such as Mad2, BubR1, and Bub3, which inhibit the APC/C when the checkpoint is active.

• Anaphase-Promoting Complex/Cyclosome (APC/C): A ubiquitin ligase that triggers the transition from metaphase to anaphase by targeting securin and cyclin B for degradation.

• Cdc20: An activator of the APC/C that is sequestered by the MCC when the checkpoint is active.

The checkpoint is activated when kinetochores are unattached or improperly attached to spindle fibers. This leads to the recruitment of checkpoint proteins to the kinetochores, forming the MCC, which binds to and inhibits Cdc20, thereby preventing the activation of the APC/C.

Regulation

The spindle checkpoint is regulated by the dynamic interactions between kinetochores and spindle microtubules. Tension generated by proper bipolar attachment stabilizes kinetochore-microtubule interactions and silences the checkpoint. Aurora B kinase and other tension-sensing mechanisms play a role in this regulation.

Clinical Significance

Defects in the spindle checkpoint can lead to aneuploidy, a condition where cells have an abnormal number of chromosomes, which is a hallmark of many cancers. Understanding the spindle checkpoint is crucial for developing therapies targeting cell division in cancer cells.

Also see

• Mitosis
• Meiosis
• Chromosome segregation
• Aneuploidy
• Kinetochores
• Anaphase-promoting complex