Cell cycle and mitosis

Cell Cycle Phases - The Cell's Day Planner

• Interphase (G1, S, G2): Longest phase, focused on growth and DNA replication.
  • G1 (Gap 1): Cell growth, protein synthesis. DNA content: $2n$. Most variable phase.
  • S (Synthesis): DNA replication occurs. DNA content: $2n \rightarrow 4n$.
  • G2 (Gap 2): Growth, organelle duplication, and DNA proofreading. DNA content: $4n$.
• M (Mitosis): Division of the nucleus.
• G0 (Quiescence): Non-dividing state. Permanent cells (neurons, cardiac muscle) remain here; stable cells (hepatocytes) can re-enter the cycle.

⭐ The G1/S checkpoint (Restriction Point) is a critical, rate-limiting step. It's regulated by tumor suppressors like Rb and p53 to prevent uncontrolled proliferation.

📌 Go Sally Go, Make Children! (G1, S, G2, M, Cytokinesis)

Cell Cycle Regulation - Cyclin' Thru Checkpoints

• Core Engine: Progression is driven by Cyclin-Dependent Kinases (CDKs), which are activated by binding to cyclins. Cyclin levels oscillate, driving the cycle forward.
• Key Checkpoints:
  • G1 → S (Restriction Point): The primary decision point. Checks for DNA damage before replication.
    • Rb Pathway: Growth factors ↑ Cyclin D/CDK4 → phosphorylates (inactivates) Rb protein → releases E2F transcription factor → S-phase gene expression.
    • p53 Pathway: DNA damage ↑ p53 → ↑ p21 (a CDK inhibitor) → hypophosphorylated Rb stays active → cell cycle arrest.
  • G2 → M: Ensures DNA replication is complete and accurate before cell division.

⭐ Li-Fraumeni syndrome, from a germline TP53 mutation, confers a high lifetime risk of various cancers (sarcomas, breast, brain, adrenal).

Mitosis Stages - The Great Cellular Divide

• Goal: To produce two genetically identical daughter cells from one parent cell.
• Maintains ploidy (e.g., diploid 2n → 2n).
• 📌 Mnemonic: Pass Me A Tissue (or PMAT)

• Prophase: Chromatin condenses into visible chromosomes (2 sister chromatids). Nuclear envelope dissolves. Spindle fibers form.
• Metaphase: Chromosomes align at the Metaphase plate.
• Anaphase: Sister chromatids separate and move to opposite poles.
• Telophase: Chromosomes decondense. Nuclear envelope reforms.

⭐ Exam Favorite: Microtubule inhibitors disrupt mitosis. Colchicine prevents microtubule polymerization, arresting cells in metaphase. This is useful for karyotyping.

Clinical Correlations - When Good Cells Go Bad

Uncontrolled cell division, the hallmark of cancer, arises from mutations in key cell cycle regulators.

• Tumor Suppressor Genes (Two-Hit Hypothesis)
  • p53 (Guardian of the Genome): Halts G1/S progression if DNA damage is detected. Mutated in >50% of human cancers.
  • Rb (Retinoblastoma): Inhibits E2F; blocks G1 → S transition.
• Proto-Oncogenes (One-Hit Hypothesis)
  • Cyclins & CDKs: Overactivation promotes cell proliferation.

⭐> Li-Fraumeni syndrome, an autosomal dominant condition, results from a germline TP53 mutation, leading to a lifetime risk of various cancers.

• Cyclin-dependent kinases (CDKs) are constitutively expressed but are activated by cyclins, which are phase-specific.
• The primary cell cycle checkpoints are at the G1/S transition (Restriction Point) and the G2/M transition.
• Key tumor suppressors p53 and retinoblastoma (Rb) protein halt the cycle at the G1/S checkpoint.
• Hypophosphorylated Rb is active and inhibits E2F, preventing S phase entry.
• S phase is for DNA synthesis; M phase is for mitosis.
• Permanent cells like neurons and cardiac muscle remain in G0.