Cell Cycle Control

• All cells are derived from pre-existing cells, no cell is derived from spontaneous generation
• Cell cycle


  1. Replication of cell material

  2. Division of replicated material into two daughter cells
• Cell cycle


  Orchestrated set of replication events
• Cell cycle


  • Replication of cell membrane, organelles, and DNA
  • Equal division of replicated material into two daughter cells
• Cell cycle control


  Regulated by cyclin-dependent kinases (CDKs) and regulatory proteins called cyclins
• Cell cycle progression


  1. Checkpoints to evaluate different processes

  2. If problems cannot be resolved, cell is programmed to die (apoptosis)
• Stages of cell cycle

  • Cell growth and chromosome duplication
  • Chromosome segregation
  • Cell division
• Phases of cell cycle

  • G1 (growth)
  • S (DNA synthesis)
  • G2 (growth)
  • M (mitosis and cytokinesis)
• Cell cycle checkpoints


  • Ensure cell division process happens flawlessly
  • Check if environment is favorable, DNA is replicated properly, chromosomes are aligned correctly
• Cyclin-dependent kinases (CDKs)


  Proteins that work in pairs with cyclins to initiate cell cycle progression
• Cyclins


  Regulatory proteins that bind to CDKs and control their activity
• Major cyclin-CDK complexes in eukaryotes

  • G1 cyclin-CDK (cyclin D-CDK4/6)
  • G1/S cyclin-CDK (cyclin E-CDK2)
  • S cyclin-CDK (cyclin A-CDK2)
  • M cyclin-CDK (cyclin B-CDK1)
• Cyclin-CDK complexes are activated by phosphorylation and deactivated by dephosphorylation
• Experiments on Xenopus oocytes (frog eggs) led to the discovery of cyclin-CDK complexes
• Cytoplasm from a cell in mitosis can induce quiescent Xenopus oocytes to enter mitosis, indicating the presence of mitosis-promoting factors
• CDKs are present throughout the cell cycle, but their activity is controlled by binding to cyclins
• Cyclins are produced and degraded at specific points in the cell cycle to control CDK activity
• G1 state


  State where the G1 CDK is formed and then declines when the cell progresses to S phase
• S cycling


  Increases in amount during the G1 phase and stays present during the S phase of the cell cycle
• M cycling


  Not present during the G1 State nor the S phase, begins to climb up a little bit during the G2 State and Peaks during M phase
• Activation of M CDK


  Binding of M cycling to M CDK at the end of the G2 phase
• Phosphorylation and Dephosphorylation


  Control the activity of the cyclin dependent kinases
• Inhibitory phosphate


  Inactivates the cyclin CDK complex
• Activating phosphate


  Activates the cyclin CDK complex
• Kinases and phosphatases involved

  • Wee1
  • Cdc25
• Activation of M CDK


  1. Binding of M cycling to M CDK

  2. Phosphorylation by Wee1 at inhibitory site

  3. Dephosphorylation by Cdc25 at activating site
• Cdc


  Cell division control proteins, mutants initially isolated from S. pombe and S. cerevisiae that control the cell cycle
• Mitotic CDK


  Also called Cdc2, contains phosphorylation sites at Tyr15 and Thr161
• Activation of Mitosis Promoting Factor (MPF)


  1. Binding of M cycling to M CDK

  2. Phosphorylation by Wee1 at Tyr15 (inhibitory)

  3. Phosphorylation by Cdc2 at Thr161 (activating)

  4. Dephosphorylation by Cdc25 at Tyr15 (activating)
• CDK Inhibitors


  Proteins like p27 that can bind to and inactivate active cyclin CDK complexes
• Transition from G2 to M

  1. DNA replicated and damage repaired

  2. Destruction of M cycling mediated by ubiquitination
• Activation of S CDK


  1. Binding of S cycling to S CDK

  2. Phosphorylation and activation

  3. Phosphorylation of Cdc6 and ORC leading to DNA replication initiation
• G0 state


  Quiescent, non-dividing cell state that cells can enter if growth factors are lacking
• Anaphase Promoting Complex (APC)


  Prevents mitosis until all chromosomes are ready to separate
• Initiation of DNA replication

  1. ORC binds to origin of replication

  2. Cdc6 binds ORC and recruits helicase

  3. S CDK phosphorylates Cdc6 and ORC, recruiting replication machinery
• DNA damage


  Activates DNA damage checkpoints to prevent cell cycle progression
• Phosphorylation of ORC


  1. Prevents ORC from being bound by CDC6

  2. Activates helicase

  3. Exports helicase out of the nucleus to prevent re-replication
• Phosphorylation of CDC6


  Targets CDC6 for ubiquitination and degradation
• Activation of cyclin-dependent kinases during S-phase helps activate DNA replication and prevent re-replication
• There are different cell cycle checkpoints