Cell Cycle Regulation and Checkpoints

Tues Week 7 Bio122

Cell cycle regulation occurs through various checkpoints and regulatory proteins. These mechanisms ensure accurate DNA replication and proper cell division.

Cyclins: Concentrations vary throughout the cell cycle.
- Specific cyclins are associated with specific stages.
- The important takeaway is that different cyclins are present at different stages of the cell cycle.
Cyclin-Dependent Kinases (CDKs): Present throughout the cell cycle.
- These require association with specific cyclins for enzymatic (kinase) activity.
- Kinase activity occurs only when CDKs bind to cyclins.
The cell cycle is the most important decision a cell can make, requiring a huge energetic investment and ensuring accurate genome replication.

CDK activity is modulated by phosphorylation.
- Phosphorylation can have inhibitory or activating effects on kinase activity.
- Inhibitory phosphorylation prevents premature entry into the next stage.
- Activating phosphorylation promotes progression through the cell cycle.

Cell cycle entry is triggered by growth factors.
Ligands bind to receptors, initiating a signaling pathway (non-GPCR-based).
Specific cyclins and proteins are produced as a result, promoting cell division.

DNA damage can halt the cell cycle.
Early Damage (G1 Phase):
- Production of p21, which inhibits CDK-cyclin complexes preventing entry into S phase.
Later Damage and Incomplete Replication:
- Triggers a similar checkpoint response.
If DNA damage is irreparable, the cell cycle arrests permanently or initiates apoptosis.

Also known as M-CDK, comprised of cyclin B and CDK1.
- Regulates the transition from G2 to M phase.
MPF activity peaks between G2 and M phases.
Targets of active MPF:
- Chromatin condensation: From loose chromosomes to condensed metaphase chromosomes.
- Nuclear envelope breakdown.
- Flattening of the Golgi apparatus and endoplasmic reticulum (ER).
- Spindle formation initiation
MPF should not be active unless replication has been successful to avoid abnormal cells.
Inhibiting the phosphatase that removes the inhibitory phosphate from MPF prevents entry into M phase if DNA damage is detected.

The cell constantly decides whether to continue dividing or undergo apoptosis.
Continuing with damaged DNA can lead to abnormal behavior, cell death, or increased oncogenic activity.

Ensures all chromosomes are correctly attached to microtubules from opposite poles (bipolar attachment).
Mechanical tension sensed at kinetochores confirms proper attachment.
Microtubules must contact chromosomes from opposite sides for stability.
This checkpoint is crucial for preventing cells with incorrect chromosome numbers.

CDC20 must be sensitive to even a single unattached kinetochore out of 92 points of contact (in humans) to prevent premature anaphase.
Low CDC20 concentration ensures high sensitivity.
Unattached kinetochores bind CDC20. Only when all kinetochores are attached does CDC20 become available in the cytosol.
Free CDC20 then binds to APC, initiating anaphase.

Cancer is a genetic disease involving accumulated mutations.
The "two-hit hypothesis" describes the process.
First "hit": A mutation increases the probability of errors during the cell cycle, reducing fidelity.
Second "hit": Additional mutations accumulate, potentially affecting checkpoints and cell cycle regulation.

Mutated genes in cancers can be divided into two categories: Oncogenes and Tumor Suppressor Genes.

Lose function when mutated.
P53:
- Most important tumor suppressor gene.
- Mutations prevent normal responses to DNA damage.
- Loss of p53 function impairs p21 production and CDK inhibition, allowing the cell cycle to continue with damaged DNA.

Not discussed explicitly but implied as the counterpart of tumor suppressor genes in cancer development.