G₀ Phase

• Non-dividing state
• Some cells permanently (neurons)
• Some temporarily (liver cells)

Mitosis

Purpose: Produce two identical daughter cells

Stages: PMAT

1. Prophase

• Chromatin condenses → visible chromosomes
• Each chromosome has 2 sister chromatids (joined at centromere)
• Centrosomes move to opposite poles
• Spindle fibers begin forming
• Nuclear envelope breaks down

2. Metaphase

• Chromosomes align at metaphase plate (cell equator)
• Spindle fibers attach to kinetochores (on centromeres)
• M checkpoint (spindle checkpoint): all chromosomes attached?

3. Anaphase

• Sister chromatids separate
• Move to opposite poles
• Cell elongates

4. Telophase

• Nuclear envelopes reform around each set of chromosomes
• Chromosomes decondense
• Spindle disappears
• Cleavage furrow begins (animals) or cell plate forms (plants)

Cytokinesis

Division of cytoplasm (overlaps with telophase)

Animals:

• Cleavage furrow forms (actin/myosin ring)
• Pinches cell in two

Plants:

• Cell plate forms from vesicles
• Builds new cell wall from center outward

Cell Cycle Regulation

Cyclins and CDKs (cyclin-dependent kinases):

• Cyclins: regulatory proteins that fluctuate in concentration
• CDKs: enzymes that phosphorylate target proteins
• Cyclin-CDK complexes drive cell cycle forward

Key regulators:

• p53: "guardian of genome"
  • Stops cycle if DNA damaged
  • Triggers apoptosis if damage severe
• Rb protein: regulates G₁ checkpoint

Checkpoints:

1. G₁: size, nutrients, DNA damage
2. G₂: DNA replication complete and accurate
3. M (spindle): all chromosomes attached to spindle

Cancer and Cell Cycle

Cancer: Uncontrolled cell division

Causes:

• Proto-oncogenes mutated → oncogenes (accelerate cycle)
• Tumor suppressor genes (p53, Rb) inactivated
• Checkpoint failures

Characteristics:

• Ignore stop signals
• Don't undergo apoptosis
• Invade other tissues (metastasis)
• Induce blood vessel formation (angiogenesis)

Key Concepts

1. Interphase: G₁, S (DNA replication), G₂
2. Mitosis (PMAT): prophase, metaphase, anaphase, telophase
3. Sister chromatids separate in anaphase
4. Checkpoints ensure proper progression
5. Cyclin-CDK complexes regulate cell cycle
6. p53 stops cycle if DNA damaged
7. Cancer results from cell cycle dysregulation

Some cells exit to G₀:

• G₀ (Gap 0): Non-dividing state
• Examples: Neurons (permanent), liver cells (can re-enter)

S Phase (Synthesis):

• Duration: 6-8 hours (typical)
• Key event: DNA replication
  • Each chromosome duplicated
  • Sister chromatids joined at centromere
  • 2n → still 2n (number of chromosomes) but DNA amount doubles
• Histone synthesis
• Centrosome duplication begins

G₂ Phase (Gap 2):

• Duration: 2-5 hours
• Activities:
  • Continued growth
  • Protein synthesis (especially for mitosis)
  • Centrosome duplication completes
  • Cell prepares for mitosis
• G₂/M checkpoint

(b) M Phase (Mitosis + Cytokinesis):

Mitosis - Nuclear division (5 stages):

1. Prophase:

• Chromatin condenses → visible chromosomes
• Each chromosome = 2 sister chromatids
• Centrosomes move to opposite poles
• Mitotic spindle begins forming
• Nuclear envelope starts fragmenting

2. Prometaphase:

• Nuclear envelope completely fragments
• Kinetochores form at centromeres
• Spindle microtubules attach to kinetochores
• Chromosomes begin moving

3. Metaphase:

• Chromosomes align at metaphase plate (cell equator)
• Kinetochores of sister chromatids attached to opposite poles
• M checkpoint (spindle checkpoint)
• All chromosomes must be attached before proceeding

4. Anaphase:

• Sister chromatids separate
• Move to opposite poles
• Spindle microtubules shorten
• Cell elongates
• Now have 2n chromosomes at each pole

5. Telophase:

• Nuclear envelopes re-form around each set
• Chromosomes decondense
• Spindle disassembles
• Cleavage furrow begins (animals) or cell plate forms (plants)

Cytokinesis - Cytoplasmic division:

• Animals: Contractile ring of actin/myosin → cleavage furrow
• Plants: Cell plate forms from Golgi vesicles → new cell wall

Result: 2 identical daughter cells (2n each if diploid parent)

(c) Cell Cycle Checkpoints:

Purpose: Ensure proper cell division, prevent errors

G₁/S Checkpoint (Restriction Point):

• Location: End of G₁, before S
• Checks:
  • Is cell large enough?
  • Adequate nutrients?
  • Growth signals present?
  • DNA damage?
• Decision:
  • ✓ Pass → Enter S phase (committed to divide)
  • ✗ Fail → Enter G₀ or undergo apoptosis

Regulation:

• CDKs (cyclin-dependent kinases) + cyclins
• p53 protein ("guardian of genome") - detects DNA damage
• Rb protein (retinoblastoma) - prevents S phase entry

G₂/M Checkpoint:

• Location: End of G₂, before mitosis
• Checks:
  • Is DNA fully replicated?
  • Any DNA damage?
  • Cell large enough?
• Decision:
  • ✓ Pass → Enter mitosis
  • ✗ Fail → Repair DNA or apoptosis

M Checkpoint (Spindle Checkpoint):

• Location: Metaphase
• Checks:
  • All chromosomes attached to spindle?
  • Kinetochores properly attached to opposite poles?
  • Proper tension on spindle fibers?
• Decision:
  • ✓ Pass → Anaphase proceeds (APC activated)
  • ✗ Fail → Wait until all attached

Molecular control:

MPF (Maturation-Promoting Factor):

• Cyclin + CDK complex
• Triggers entry into M phase
• Phosphorylates proteins needed for mitosis

Cyclin levels fluctuate:

Cyclin
 level
   ^     /\         /\
   |    /  \       /  \
   |   /    \     /    \
   |  /      \   /      \
   |_/________\_/_________> Time
     G1  S  G2 M  G1  S  G2 M

Cancer connection:

• Mutations in checkpoint genes → uncontrolled division
• p53 mutations: ~50% of cancers
• Rb mutations: retinoblastoma, other cancers

$\boxed{\text{Checkpoints ensure: DNA integrity, proper replication, correct chromosome attachment}}$