The Cell Cycle: Stages and Regulation

The Cell Cycle: Stages and Regulation

• G1 Phase: Cell growth and preparation for DNA replication
  • Cyclin D-CDK 4/6 complexes initiate the G1 phase, promoting the synthesis of proteins needed for S phase.
  • Phosphorylation of the retinoblastoma protein (Rb) releases E2F transcription factors, allowing S phase entry.
• G1/S Checkpoint: Ensures the cell is ready for DNA replication
  • Cyclin E-CDK 2 complex further phosphorylates Rb, bolstering E2F release and initiating DNA replication.
  • This complex also activates proteins involved in pre-replication complex formation.
• S-Phase: DNA replication
  • Cyclin A-CDK 2 complex drives DNA synthesis, ensuring accurate and efficient replication.
  • This complex prevents re-replication by inhibiting pre-replication complex formation.
• G2 Phase: Cell preparation for mitosis
  • Cyclin A-CDK 1 complex triggers chromatin condensation and activates mitotic proteins.
• G2/M Checkpoint: Ensures DNA is properly replicated and ready for mitosis
  • Cyclin B-CDK 1 complex (Maturing Promoting Factor, MPF) controls the transition to M phase.
  • MPF regulates critical events like nuclear envelope breakdown, chromosome condensation, spindle formation, and chromosome alignment.
  • CDK 1 activation relies on precise phosphorylation events.
• M-Phase: Cell division
  • Cyclin B-CDK 1 complex remains active during prophase, metaphase, and anaphase, driving mitotic events.
  • Degradation of Cyclin B by the anaphase-promoting complex/cyclosome (APC/C) enables the completion of mitosis and cytokinesis.

Factors that Drive Cell Cycle Progression

• Cyclins: Regulate cell cycle progression by activating cyclin-dependent kinases (CDKs). Their levels fluctuate throughout the cycle.
• Cyclin-Dependent Kinases (CDKs): Enzymes activated by cyclins to phosphorylate target proteins.
• CDK Inhibitors (CKIs): Serve as checkpoints, halting the cell cycle in response to DNA damage or stress.
• Growth Factors: Promote cell division and survival by initiating signaling pathways that regulate cell cycle progression.
• Tumor Suppressor Proteins: Act as negative regulators to suppress uncontrolled cell proliferation. Examples include p53 and Rb.
• Oncogenes: Mutated or overexpressed genes that drive uncontrolled cell proliferation. Examples include genes encoding growth factor receptors and signaling proteins like Ras.
• DNA Damage & Repair Mechanisms: Cells activate checkpoint pathways to arrest the cell cycle and facilitate DNA repair.
• Cell Cycle Checkpoints: Control mechanisms that ensure proper progression only when conditions are favorable.
• Mitogens: Induce cell division by stimulating the transition from quiescence (G0) to G1 phase.
• Nutrient Availability: Adequate nutrients and energy are crucial for cell growth and division, monitored by signaling pathways.

Drugs that Interfere with the Cell Cycle

• Antimetabolites: Mimic natural substances, interfering with DNA and RNA synthesis.
  • Methotrexate: Inhibits nucleotide synthesis.
  • 5-fluorouracil (5-FU): Inhibits DNA synthesis.
  • Cytarabine: Inhibits DNA polymerase.
• Mitotic Inhibitors: Disrupt microtubule function, inhibiting mitosis.
  • Paclitaxel (Taxol): Stabilizes microtubules.
  • Vincristine and Vinblastine: Inhibit microtubule assembly.
• Topoisomerase Inhibitors: Interfere with the enzymes that control changes in DNA structure for replication.
  • Doxorubicin: Inhibits topoisomerase II.
  • Etoposide: Inhibits topoisomerase II.
• Alkylating Agents: Add alkyl groups to DNA, leading to damage and apoptosis.
  • Cyclophosphamide: Cross-links DNA strands.
  • Cisplatin: Forms DNA adducts, causing cross-linking.
• Antitumor Antibiotics: Intercalate into DNA, disrupting transcription and replication.
  • Doxorubicin (Adriamycin): Intercalates into DNA.
  • Bleomycin: Causes DNA breaks.
• CDK Inhibitors: Inhibit cyclin-dependent kinases, crucial for cell cycle progression.
  • Palbociclib: Inhibits CDK 4 & 6.
  • Ribociclib: Inhibits CDK 4/6.
• Proteasome Inhibitors: Inhibit the proteasome, accumulating damaged proteins and causing cell cycle arrest.
  • Bortezomib: Inhibits the 26s proteasome.

Targeting CDK 4/6 in Cancer Therapy

• Inhibiting CDK 4/6 is a strategy for controlling cell proliferation and potentially halting tumor growth.
• Inhibitors like Palbociclib, Ribociclib, and Abernacyclic are used in hormone-driven breast cancer.

Side Effects of Cell Cycle Inhibitors

• Bone marrow suppression: Reduces blood cell production.
• Diarrhea:Due to continuous cell division in the gut.

BRCA 1/2 and Checkpoint Mutations:

• BRCA 1 and BRCA 2 participate in DNA repair (especially homologous recombination) and cell cycle regulation.
• Mutations in these genes disrupt DNA repair and contribute to cancer development, particularly breast and ovarian cancers.

BRCA 1/2 and Cell Cycle Checkpoints:

• G1/S Checkpoint: BRCA 1 plays a role in repairing double-strand DNA breaks. Mutations may bypass this checkpoint.
• G2/M Checkpoint: Both BRCA 1/2 are crucial for ensuring DNA damage repair before mitosis. Mutations can impair this checkpoint.

Impact of BRCA 1/2 Mutations on Checkpoints:

• Loss of function in BRCA 1/2 proteins leads to impaired DNA repair and checkpoint failure, allowing cells with DNA damage to progress through the cell cycle.

Genomic Instability:

• The failure of checkpoints due to BRCA 1/2 mutations leads to genomic instability, a hallmark of cancer, promoting tumorigenesis.

Clinical Implications:

• BRCA 1/2 mutations increase the risk of developing cancers, especially breast and ovarian cancers.
• Individuals with these mutations are candidates for targeted therapies like PARP inhibitors.

PARP Inhibitors:

• Target enzymes involved in single-strand break (SSB) DNA repair.
• Exploit defective DNA repair mechanisms in cells with BRCA mutations, leading to cell death.

Summary:

• The cell cycle is tightly regulated to ensure proper growth and division.
• Understanding cell cycle regulation is crucial for developing cancer therapies that target specific points in this process.