2. the cell cycle #2

• Cell cycle control is essential due to the complex system of coordinated processes that must occur in a specific sequence
• Regulatory proteins and biochemical switches control progression through the cell cycle
• Regulatory proteins act as molecular switches, allowing cells to progress through the cell cycle or pause for repair or preparation for the next phase
• The cell cycle control system monitors intracellular and extracellular environments
• Cyclin-Dependent Kinases (CDKs) are key regulators of the cell cycle
• CDKs' activity is dependent on the presence of cyclin proteins
• CDKs, along with cyclins, act as molecular switches controlling various processes in the cell cycle
• CDKs regulate critical events such as DNA replication, mitosis, chromosome segregation, and cell proliferation
• There are four major classes of cyclins: G1/S Cyclins, S-Cyclins, M-Cyclins, and G1-Cyclins
• G1/S Cyclins are crucial for the transition from the G1 phase to the S phase of the cell cycle
• 1. Cyclins are essential for DNA replication during the S phase
• 1. Cyclins promote events associated with mitosis
• G1-Cyclins promote the passage through the restriction point in late G1 phase
• CDKs are protein kinases that add phosphate groups to proteins, altering their activity
• Phosphorylation is the addition of a phosphate group that can activate or deactivate target proteins
• Protein phosphatase is an enzyme that removes phosphate groups, reversing phosphorylation effects
• The balance between kinase and phosphatase activity is crucial for cellular processes
• CDK activity is regulated through protein degradation
• Ligases are enzymes responsible for degrading cyclins, leading to decreased activity
• Cell cycle control involves M Cyclins and S Cyclins that rise during specific phases and contribute to cell cycle progression
• Activation of CDKs involves a multi-step process including cyclin binding and phosphorylation by CDK Activating Kinase (CAK)
• Inhibition of CDKs involves the addition of an inhibitory phosphate, which can be removed by protein phosphatase
• Ubiquitin Ligases are crucial for controlling the levels of cyclins and CDKs by marking them for destruction in the proteasome
• SCF Ligase can lead to the destruction of G1/S cyclins and CKI
• APC Ligase can lead to the destruction of securin and M-cyclin
• SCF and APC are active during different stages of the cell cycle, regulating the progression of the cell cycle
• CDC20 activates APC, leading to the destruction of M-cyclin and a subsequent reduction in active M-CDK levels, essential for exiting Mitosis
• Reduction in active M-CDK levels negatively affects APC-CDC20, reducing its activity levels
• Low levels of active M-CDK activate APC-CDH1, ensuring a sustained reduction in M-cyclin levels
• APC-CDH1 is crucial for maintaining low M-cyclin levels during the G1 phase to prevent premature entry into Mitosis
• There are two forms of APC, each with specific activation and deactivation dynamics
• APC activity dynamics ensure precise control over cell cycle progression, both in entering and exiting Mitosis
• Activation of M-Cdk triggers Mitosis:

  • In late G2 phase, M-cyclin binds to CDK1, forming the M-CDK complex
  • CDK1 undergoes conformational changes and is phosphorylated by CAK, making it partially active
  • Wee1 phosphorylates M-CDK at an inhibitory site, placing it in an inactive state
  • Cdc25 removes the inhibitory phosphate added by Wee1, activating M-CDK
  • Active M-CDK initiates a positive feedback loop, phosphorylating and activating more Cdc25, amplifying M-CDK activity
• Basal Activation by SCdk contributes to the activation of Cdc25 during M phase, providing a basal level of Cdc25 activation before critical M-CDK buildup
• Checkpoints:

  • DNA Replication Checkpoint (End of G2 Phase)
  • Spindle Attachment Checkpoint (Metaphase)
  • DNA Damage Checkpoint (End of G1 Phase)
• DNA Replication Checkpoint:

  • Ensures all DNA is accurately and completely replicated before entering mitosis
  • Prevents cells from dividing with damaged or incompletely replicated DNA
  • Pauses cell progression until replication is completed or errors are fixed
• Spindle Attachment Checkpoint:

  • Monitors correct attachment of chromosomes to spindle fibers during metaphase
  • Inhibits progression to anaphase if chromosomes are unattached or improperly attached
  • Prevents unequal distribution of genetic material to daughter cells
• DNA Damage Checkpoint (G1):

  • Detects DNA damage before DNA replication in S phase
  • Halts progression into S phase if DNA damage is detected
  • Allows time for repair mechanisms to fix DNA lesions
• Chromatid Separation:

  • Activation of APC by CDC20 and MCDK
  • Ubiquitination by APC, marking proteins like Securin for destruction
  • Degradation of Securin by the proteasome, releasing Separase
  • Activation of Separase, cleaving protein complexes holding sister chromatids together
  • Sister chromatids separate, ensuring equal distribution of genetic material to daughter cells
• Spindle Attachment Checkpoint:

  • Monitors proper attachment of chromosomes to spindle fibers
  • Inhibits premature anaphase by inhibiting CDC20-APC complex activity
  • Prevents unequal distribution of genetic material due to chromosome misalignment