Retta - L11

Cell Cycle Checkpoints

• Checkpoints regulate transitions between cell cycle phases by assessing internal and external factors.
• Major checkpoints ensure DNA integrity, chromosomal attachment, and overall cell cycle conditions.
• If unfavorable conditions exist, checkpoints pause the cell cycle until issues like DNA damage are repaired.

Mechanisms of Checkpoints

• Checkpoints use negative signals to halt the cell cycle until conditions are favorable, rather than removing positive signals.
• Unattached chromosomes generate negative signals that prevent cell cycle progression until all chromosomes are correctly attached.
• DNA replication must be complete for the cell cycle to progress; incomplete DNA results in a stop signal.

DNA Damage and Checkpoint Regulation

• ATM and ATR proteins sense DNA damage like double-strand breaks and single-strand lesions during S or G2 phases.
• Activated ATM/ATR initiates p53 activation, which can block cell cycle progression or induce apoptosis if damage is irreparable.
• External factors like radiation can cause mutations affecting checkpoint functionality, potentially leading to cancer development.

Reactive Oxygen Species (ROS) and DNA Damage

• ROS, both endogenous and environmental, can induce DNA damage through oxidation.
• Excessive DNA damage may trigger apoptosis or allow for abnormal cell survival, leading to potential cancerous growth.

Radiotherapy as a Cancer Treatment

• Radiotherapy induces extensive DNA damage to trigger apoptosis in cancer cells.
• Some cells repair and survive DNA damage, facilitating cancer progression despite treatment efforts.

Cyclin-Dependent Kinases (CDKs) Regulation

• Cyclins activate CDKs by binding to them, initiating specific cell cycle processes.
• CDK activity is temporally regulated, with cyclin concentrations varying throughout the cell cycle.
• Cyclin-CDK complexes are critical for transitions between cell cycle phases, impacting key events like DNA replication and mitosis.

Cyclins and Their Functions

• M-cyclin drives entry into M phase; S-cyclin triggers DNA replication initiation.
• Cyclin concentrations peak just before their functional phase and degrade post-usage.

G1/S Cyclin and External Signals

• G1 cyclin activates G1/S-Cdk, which promotes S phase entry upon sensing growth factors and nutrients.
• APC/C checks chromosomal attachment during mitosis, ensuring cell cycle integrity.

CDK Inhibition Mechanisms

• CDK complexes can be inhibited through additional phosphorylation by Wee1 kinase.
• Cdc25 phosphatase reactivates CDK by removing inhibitory phosphate groups.

CDK Inhibitor Proteins (CKIs)

• CKIs like p21, p16, and p27 inhibit CDK activity, providing additional regulatory control for cell cycle progression.
• P53 activation leads to CKI expression, which prevents entry into the cell cycle when DNA damage occurs.

Role of Proteolysis in Cell Cycle Control

• Ubiquitination targets cyclins for degradation via the proteasome to regulate their availability throughout the cell cycle.
• This cyclical proteolysis mechanism ensures proper timing of cell cycle phase transitions and prevents uncontrolled proliferation.