The Cell Cycle

• Cell cycle


  The cycle of events that a cell goes through, including growth, DNA replication, and cell division
• Cell cycle protein


  A protein involved in regulating the cell cycle
• Purpose of checkpoints


  • Multiple checkpoints in the eukaryotic cell cycle ensure that division occurs only after sufficient growth and faithful DNA replication, and only when favorable conditions exist
  • At each checkpoint, numerous proteins engage in a series of carefully coordinated biochemical reactions
  • This complexity allows for precise regulation of all steps in the cell cycle
• Interphase


  1. G1 (gap 1 or growth phase)

  2. S (synthesis - DNA replication)

  3. G2 (gap 2 - has everything gone well during S phase)
• Mitosis


  1. Prophase

  2. Metaphase

  3. Anaphase

  4. Telophase
• Cancer prevents or goes past the checkpoints leading to uncontrolled cell growth
• 6 essential alterations in cell physiology that collectively dictate malignant growth

  • Self sufficiency in growth signalling
  • Loss of cell proliferation inhibition
  • Evasion of apoptosis
  • Unlimited replicative potential
  • Angiogenesis
  • Invasion and metastasis
• Cyclin


  Proteins made and destroyed in a pattern depending on the cell cycle phases
• Cyclin-dependent kinases (CDKs)


  Proteins that control the cell cycle via phosphorylation of other proteins
• Regulation of CDK by phosphorylation/dephosphorylation

  1. Active CDK = dephosphorylated CDK

  2. Inactive CDK = phosphorylated CDK
• DNA damage


  Activates CDC25C which dephosphorylates and activates cyclin-B1-CDK1, initiating mitotic events
• Cell cycle checkpoints


  • Checkpoint at late G1 (restriction point)
  • Checkpoint at G2/M transition
  • Checkpoint during mitosis (spindle checkpoint)
• CDC genes (cell division cycle genes) are involved in cell cycle checkpoints
• CDC gene


  Cell division cycle genes involved in checkpoints
• Cell cycle is arrested when DNA is damaged


  Allows DNA to repair itself before the cell continues to the next phase of the cycle
• These findings led to important insights into how cancer cells develop
• 3 cell cycle checkpoints

  • Checkpoint at late G1 (restriction point/start point in yeast)
  • DNA damage checkpoint after G2
  • M or metaphase checkpoint
• Restriction point


  Checkpoint at late G1 that checks size, nutrients, growth factors, and critical mass before committing to cell cycle completion
• DNA damage checkpoint after G2

  Ensures chromosomes are replicated properly and DNA is not damaged
• M or metaphase checkpoint


  Ensures chromatids are correctly attached to the spindle for efficient separation
• Purpose of cell cycle checkpoints

  • Prevent catastrophic progression of the cell cycle
  • Detect DNA damage and extracellular conditions
  • Detect if replication is incomplete
• If checkpoint detects incomplete replication

  CDC25 is inhibited, preventing CDK-cyclin from being dephosphorylated and keeping it inactive
• Cdk inhibitors (CKIs)


  Proteins that negatively regulate Cdks by binding to the Cdk-cyclin complex and masking the substrate site
• How to remove the CKI block to proceed cell cycle

  Ubiquitination and proteosome degradation removes CKI from the cyclin-CDK complex, activating the kinase
• Molecules involved in the cell cycle

  • CKIs (red)
  • Kinases and their activators (green)
• DNA damage (ds break or thymidine dimers) checkpoint mechanisms and induction pathway

  Can lead to cell cycle arrest or progression after damage is repaired
• p53


  Regulates the DNA repair process and apoptosis
• Endoreduplication


  When cells do not divide but continuously make DNA, resulting in polyploid cells with more than 2n DNA
• Many tumours are polyploid due to endoreduplication
• Endomitosis


  Cell cycle that displays features of mitosis but lacks cytokinesis
• Endocycling


  Cell cycle with alternating S and G phases without cell division
• Endoreplication can promote genome instability and is an attempt by tumour cells to avoid drug treatment
• Unscheduled whole-genome duplications leading to tetraploid cells occur in a substantial fraction of human tumours
• Polyploid cells contribute to solid tumour heterogeneity but their functions are largely undefined
• Endoreduplication is controlled by the same cell cycle regulators that drive diploid cell cycle and is highly conserved in evolution
• Polyploidy contributes to stress response and pathogenesis
• TP53 is a critical tumour suppressor gene that regulates cell cycle progression, apoptosis, cellular senescence, and other properties critical for normal cellular growth and death
• TP53 mutations are frequently detected in numerous cancers