Spindle checkpoint

Cell Cycle 2-2

Spindle chromosomes-en

Metaphase anaphase

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Three cell growth types

File:Chromosome bipolar attachments.jpg

Chromosome bipolar attachments

Kinetochore

== Spindle Checkpoint ==

The spindle checkpoint is a crucial cell cycle control mechanism that ensures proper chromosome segregation during mitosis. 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, thereby keeping the cohesin complex intact and preventing the separation of sister chromatids.

Key Proteins

• Mad1 and Mad2: These proteins form a complex that is essential for the spindle checkpoint. Mad2 undergoes a conformational change upon binding to Mad1, which is crucial for its checkpoint function.
• Bub1 and Bub3: These proteins are involved in the recruitment of other spindle checkpoint proteins to the kinetochores.
• Mps1: A kinase that phosphorylates various spindle checkpoint proteins, enhancing their activity.

Consequences of Checkpoint Failure

Failure of the spindle checkpoint can lead to chromosomal instability (CIN) and aneuploidy, which are hallmarks of many cancers. Cells that bypass the spindle checkpoint may proceed through mitosis with misaligned or unattached chromosomes, resulting in daughter cells with unequal chromosome numbers.

Research and Clinical Implications

Understanding the spindle checkpoint is critical for developing therapeutic strategies against cancer. Inhibitors targeting spindle checkpoint proteins are being explored as potential cancer treatments, as they can selectively kill cancer cells with high levels of chromosomal instability.

Related Pages

• Cell cycle
• Mitosis
• Chromosome
• Kinetochore
• Anaphase
• Anaphase-promoting complex/cyclosome
• Aneuploidy
• Genomic stability
• Cancer