Recording-2025-03-13T08:22:46.873Z

Overview of Cell Cycle Checkpoints

• Definition: Cell cycle checkpoints act as stop signs that regulate progression through the cell cycle, ensuring cells do not divide uncontrollably.

• Importance: Uncontrolled cell division can lead to tumor formation and cancer.

Types of Checkpoints

1. G1 Checkpoint

• Occurs at the end of the G1 phase.

• Function: Prevents cell from entering S phase until there is sufficient growth factor.

• Growth Factor: External molecules that bind to cell membrane proteins, signaling it's time to grow.

• Mechanism: If growth factors are adequate, the checkpoint allows the cell to proceed to DNA replication (S phase).

2. G2 Checkpoint

• Occurs at the end of the G2 phase.

• Function: Ensures DNA has been accurately replicated before entering mitosis.

• Mechanism: If DNA damage or replication errors are detected, the checkpoint holds up progress to prevent mutations from passing on to daughter cells.

3. M Checkpoint

• Occurs during mitosis.

• Function: Monitors chromosome attachment to the mitotic spindle.

• Mechanism: The checkpoint remains active (stop sign) until all chromosomes are properly attached, preventing uneven chromosome distribution in daughter cells.

Mechanisms of Checkpoint Regulation

• Proteins Involved: Cyclins and Cyclin-Dependent Kinases (CDKs) regulate the checkpoints.

Cyclins

• Characteristics: Degrade rapidly and are produced at specific cell cycle phases.

• Examples:

  • Cyclin E: Peaks at the end of G1 phase, important for G1 checkpoint.

  • Cyclin A: Peaks during G2 phase, crucial for the G2 checkpoint.

  • Cyclin B: Peaks during M phase, regulates the M checkpoint.

Cyclin-Dependent Kinases (CDKs)

• Characteristics: Kinases that require cyclin to be active.

• Function: Add phosphate groups to target proteins, promoting checkpoint advancement when activated by their respective cyclin.

Example of Checkpoint Function: G1 Checkpoint

• Key proteins: Retinoblastoma gene product (RB) and E2F transcription factor.

• Mechanism: RB binds to E2F, preventing it from activating genes required for S phase entry.

• Activation: When CDK is activated, it phosphorylates RB, releasing E2F, which allows the cell to proceed to S phase.

• Relevance to Cancer:

  • Proto-Oncogene: E2F (promotes cell cycle progression). Mutated E2F can lead to cancer if RB can't inhibit it.

  • Tumor Suppressor Gene: RB inhibits progression but, if mutated, can no longer bind E2F, leading to uncontrolled cell division.

Implications of Mutations in Checkpoint Proteins

• Proto-Oncogenes vs. Tumor Suppressor Genes:

  • Proto-oncogenes (e.g., CDKs, cyclins) promote cell cycle progression; mutations can lead to cancer.

  • Tumor suppressor genes (e.g., RB, p53) inhibit cell cycle progression; mutations remove this control, increasing cancer risk.

• Retinoblastoma: Specific cancer linked to RB mutations; in many cancer cells, mutations in both proto-oncogenes and tumor suppressor genes are common.