Spindle checkpoint

File:Chromosome bipolar attachments.jpg

Spindle checkpoint

The spindle checkpoint is a crucial cell cycle control mechanism that ensures proper chromosome segregation during mitosis and meiosis. This checkpoint prevents the onset of anaphase until all chromosomes are correctly attached to the mitotic spindle via their kinetochores. The spindle checkpoint helps maintain genomic stability by preventing aneuploidy, a condition where cells have an abnormal number of chromosomes.

Mechanism

The spindle checkpoint operates by monitoring the attachment of chromosomes to the spindle microtubules and the tension generated at the kinetochores. Key proteins involved in this process include Mad1, Mad2, Bub1, Bub3, and Mps1. These proteins form a complex that inhibits the 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.

When kinetochores are not properly attached to spindle microtubules, the spindle checkpoint proteins generate a "wait" signal that inhibits the APC/C. This inhibition prevents the degradation of securin, which in turn inhibits the activity of separase, an enzyme required for the cleavage of cohesin complexes that hold sister chromatids together. Once all chromosomes are correctly attached and under tension, the checkpoint is satisfied, leading to the activation of APC/C, degradation of securin, activation of separase, and the onset of anaphase.

Key Proteins

• Mad1 and Mad2: These proteins form a complex that is essential for the spindle checkpoint. Mad2, in particular, undergoes a conformational change upon binding to unattached kinetochores, which is crucial for its inhibitory function on APC/C.
• Bub1 and Bub3: These proteins are involved in the recruitment of other spindle checkpoint proteins to the kinetochores and play a role in the inhibition of APC/C.
• Mps1: This kinase is required for the proper functioning of the spindle checkpoint by phosphorylating various substrates involved in the checkpoint signaling pathway.

Clinical Significance

Defects in the spindle checkpoint can lead to chromosomal instability (CIN), which is a hallmark of many cancers. Cells with a defective spindle checkpoint may undergo mitotic slippage, leading to aneuploidy and tumorigenesis. Understanding the molecular mechanisms of the spindle checkpoint is crucial for developing targeted therapies for cancers characterized by chromosomal instability.

Research and Future Directions

Ongoing research aims to elucidate the detailed molecular interactions and regulatory mechanisms of the spindle checkpoint. Advances in this field could lead to the development of novel therapeutic strategies to enhance the fidelity of chromosome segregation in cancer cells, potentially reducing the incidence of aneuploidy and improving patient outcomes.

See Also

• Cell cycle
• Mitosis
• Meiosis
• Chromosome segregation
• Anaphase-promoting complex/cyclosome
• Aneuploidy
• Cancer