mitotic DNA integrity checkpoint signaling

Definition

Target type: biologicalprocess

A signaling process that controls cell cycle progression in response to changes in DNA structure by monitoring the integrity of the DNA during mitosis. The DNA integrity checkpoint begins with detection of DNA damage, defects in DNA structure or DNA replication, and ends with signal transduction. [GOC:mtg_cell_cycle]

The mitotic DNA integrity checkpoint, also known as the spindle assembly checkpoint, is a critical surveillance mechanism that ensures accurate chromosome segregation during cell division. This checkpoint monitors the proper attachment of chromosomes to microtubules, preventing premature entry into anaphase and ensuring that each daughter cell receives a complete set of chromosomes. If errors are detected, the checkpoint triggers a signaling cascade that arrests the cell cycle in metaphase, providing time for the errors to be corrected.

The checkpoint relies on a complex network of proteins that interact with microtubules, chromosomes, and the cell cycle machinery. Key components include:

* **Sensors:** These proteins, such as Mad1, Mad2, and Bub1, bind to unattached kinetochores, the protein complexes that connect chromosomes to microtubules.
* **Signaling molecules:** These proteins, such as Mad2 and BubR1, transmit the signal of unattached kinetochores to downstream effectors.
* **Effectors:** These proteins, such as the mitotic checkpoint complex (MCC), inhibit the anaphase-promoting complex/cyclosome (APC/C), a ubiquitin ligase responsible for initiating the degradation of key proteins required for anaphase onset.

The checkpoint operates as follows:

1. **Unattached kinetochores:** When a kinetochore is not properly attached to a microtubule, it acts as a signal for the checkpoint.
2. **Sensor activation:** Sensors like Mad1 and Mad2 bind to unattached kinetochores.
3. **Signal transmission:** Mad2, activated by its interaction with Mad1, interacts with BubR1 and other components to form a complex.
4. **MCC assembly:** The Mad2-BubR1 complex, along with other proteins, assembles into the MCC.
5. **APC/C inhibition:** The MCC binds to and inhibits the APC/C, preventing the degradation of proteins required for sister chromatid cohesion and other mitotic processes.
6. **Cell cycle arrest:** The inhibition of APC/C activity prevents the cell from entering anaphase, allowing time for the kinetochore attachments to be corrected.

Once all kinetochores are properly attached to microtubules, the signal for the checkpoint is eliminated, the MCC dissociates from the APC/C, and the cell cycle resumes.

The mitotic DNA integrity checkpoint is essential for maintaining genome stability and preventing aneuploidy, which can lead to cancer and other developmental disorders. Defects in checkpoint proteins can cause chromosome instability and increase the risk of tumor formation. Therefore, understanding the molecular mechanisms of the checkpoint is crucial for developing strategies to combat cancer and other diseases.'
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