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Unregulated cell cycle causes
Mutations in 3 main checkpoints can lead to de-regulated cycling >> lead to disease
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S to G2 checkpoint
- Protein important in controlling replication and repair
- These are PIKK related kinases, including…
- ATR (focus of studying)
- ATM
- DNA-PK
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Role of ATR
- Essential in replicating of mammalian cells
- In S Phase: aids in initiation of replication, stability of replisome and replication fork restart
- In G2: (focus of study) prevents premature mitotic entry in presence of DAMAGED DNA
- Fxns as UPSTREAM regulator of p53 phosphorylation
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Role of p53
- Tumor suppressor protein
- Protects against propagation of cells that have DNA damage w/ potential oncogene mutations
- Phosphorylation of p53 = release from MDM-2
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Role of MDM2
- Suppressive function: Limits p53 growth in unstressed cells
- Monoubiquitinates p53 >> leading to its degradation
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p53 MDM-2 binding
- bound in both their amino-terminal domains
- p53 resides in hydrophobic pocket of MDM-2 amino terminal where it is BLOCKED from transcription machinery
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Consequence of NO p53 phosphorylation
- Possibly from MUTATION in ATR
- Can lead to unregulated cell growth of NON-VIABLE cells, as G2 >> M checkpoint is lost
- Seckel Syndrome can result >>> severe dwarphism, mental retardation, uncontrolled cell proliferation
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Role of extra centrosomes in chromosome instability
- Caused by multipolar spindle formation, which promotes MEROTELY
- Centrosomes CLUSTER at 2 poles
- Bipolar Anaphase occurs w/chromosome lagging
- Cohesion defects
- Mitotic checkpoint defects
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Result of extra centromeres in chromosome
ASSYMETRIC chromosome segregation >> results in severe Aneuploidy
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Merotely
- Kinetichores attach to SPINDLE tubules from DIFFERENT poles, causing:
- Chromosome lagging
- Chromosome damage
- Missegregation and aneuploidy
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Causes of extra centromeres
- Centriole duplification, caused by VIRAL infection OR Overexpression of:
- 1. PLK4 or
- 2. Aurora A Kinase
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PLK4
- Required for centriole duplification
- 26S proteasome degrade this…so by INHIBITING this, you have centriole overduplification
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Multipolar mitosis
- Rare occurances
- Cells that divide through this have LOW VIABILITY
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Chromosome instability definitions
- Increased rate of chromosome missegregation during cell division
- Gain (or Loss) of chromosome: Aneuploidy
- Failure to maintain correct chrom. Complement: euploidy
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