Spindle checkpoint: Difference between revisions

Latest revision as of 15:38, 9 December 2024

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[edit]

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[edit]

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[edit]

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[edit]

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[edit]

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-[[file:Cell_Cycle_2-2.svg|thumb|Cell Cycle 2-2]] [[file:Spindle_chromosomes-en.png|thumb|Spindle chromosomes-en|left]] [[file:Metaphase_anaphase.png|thumb|Metaphase anaphase]] [[file:Three_cell_growth_types.png|thumb|Three cell growth types|left]] [[file:Chromosome_bipolar_attachments.jpg|thumb|Chromosome bipolar attachments]] [[file:Kinetochore.jpg|thumb|Kinetochore]] == Spindle Checkpoint ==
+[[File:Cell Cycle 2-2.svg|thumb]] [[File:Spindle chromosomes-en.png|thumb]] [[File:Metaphase anaphase.png|thumb]] [[File:Three cell growth types.png|thumb]] 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 [[kinetochore]]s. The spindle checkpoint helps maintain [[genomic stability]] by preventing [[aneuploidy]], a condition where cells have an abnormal number of chromosomes.
+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.
-=== Mechanism ===
+== Overview ==
-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.
+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.
-=== Key Proteins ===
+== Mechanism ==
-* '''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 ===
+The spindle checkpoint involves several key proteins and complexes:
-Failure of the spindle checkpoint can lead to [[chromosomal instability]] (CIN) and aneuploidy, which are hallmarks of many [[cancer]]s. 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 ===
+* '''Kinetochores''': These are protein structures on the chromosome where spindle fibers attach. They play a critical role in sensing attachment and tension.
-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.
+* '''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 ==
-== Related Pages ==
-* [[Cell cycle]]
 * [[Mitosis]]
-* [[Chromosome]]
+* [[Meiosis]]
-* [[Kinetochore]]
+* [[Chromosome segregation]]
-* [[Anaphase]]
-* [[Anaphase-promoting complex/cyclosome]]
 * [[Aneuploidy]]
-* [[Genomic stability]]
+* [[Kinetochores]]
-* [[Cancer]]
+* [[Anaphase-promoting complex]]
+{{Cell cycle}}
+{{Molecular biology}}
 [[Category:Cell cycle]]
-[[Category:Cell biology]]
+[[Category:Molecular biology]]
 [[Category:Genetics]]
-[[Category:Cancer research]]
-{{Cell-biology-stub}}