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The Cell Cycle
Transcript of The Cell Cycle
Cell produces G1-cyclin, which makes active G1-CDK
S-cyclin is synthesized but not active, due to CKI binding to it and inhibiting its activity DNA
ORCs are assembled on the origins of replication
Cdc6 binds to the ORCs and recruits DNA Helicase Initiation of DNA Replication Alberts 17-23 CKIs are removed from G1/S-Cdk
This activates G1/S-Cdk
The CKIs are ubiquitinated and sent to the proteosome for degradation
A spike in G1/S-Cdk causes the cell cycle to exit G1 phase and enter S phase
G1/S-Cdk promotes more transcription of G1/S-cyclin and S-cyclin Cyclin-Cdk complexes can be inhibited by cyclin/kinase/inhibitors (CKI) SCF is a E3 ubiquitin ligase that adds ubiquitin to CKI but only if CKI has been phosphorylated CKIs are also destroyed by the Proteasome Alberts 17-20 S Phase POSITIVE FEEDBACK LOOP
The concentration of E2F upregulates G1/S-cyclin and S-cyclin
G1/S-Cdk and S-Cdk activity increase as the cyclins bind to CDKs
Both active CDKs upregulate the phosphorylation (deactivation) of Rb which unbinds E2F. DNA SYNTHESIS
S-Cdk phosphorylates Cdc6, which is then ubiquitinated
S-Cdk also phosphorylates ORC
PURPOSE OF DOUBLE PHOSPHORYLATION- PREVENTS REPLICATION OCCURING TWICE! Initiation of DNA Replication G2 Phase M-cyclin begins to be synthesized at the start of G2 which binds to CDK to form M-Cdk (aka MPF). However, MPF remains inactive until the completion of the G2 checkpoint. The concentration of MPF steadily rises. Phosphorylation/Dephosphorylation occurs at an ‘inactivating site’ on Cdk Two main regulatory proteins of M-Cdk are Wee1 and Cdc25 DNA is damaged /
Replication is not finished Cell cycle arrest Cell enters Mitosis M-Cdk (in the nucleus)
is Activated Cdc25 is imported to Nucleus DNA is repaired /
Replication is completed M-Cdk (in the nucleus) cannot be Activated Export of Cdc25 from nucleus to cytoplasm The G2 Checkpoint:
Stop the cycle if DNA is damaged or
DNA Replication is not finished Wee1 Kinase phosphorylates the inhibitory site
Cdc25 Phosphatase removes the P from the inhibitory site
CAK phosphorylates the active site The cell checks for DNA damage and completion of replication. When ready to start mitosis, Cdc25 removes the inhibitory phosphate. G2 Checkpoint MITOSIS Prophase 1. Chromosome condensation
Condensin- forms a ring complex, loops DNA around and through the ring
Early in prophase, condensin is activated by phosphorylation by M-Cdk
DNA is compacted by condensins, and dense DNA complexes are held together by cohesins 2. Nuclear envelope disintegration
M-Cdk phosphorylates lamins, triggers laminin breakdown
Phosphates prevent lamins to bind together 3. Centrioles
Split to opposite poles of the cell by forming the MT spindle
Astral MTs use dyenin on the cell membrane to position the centrioles
MTs are not capped at the minus end, causes treadmilling
Stabilized by KRP (+) and (-) on overlapping MTs Loaded during DNA Replication Alberts 17-24 Daughter DNA strands are held together by Cohesins SMC proteins similar to those found in Cohesins Activated by phosphorylation by M-Cdk Alberts 4-73 & 17-27 Chromosome condensation is caused by Condensins Lamins are intermediate filament proteins M-Cdk Alberts 12-21 See Alberts 17-29 & 17-31 Centriole duplication is semiconservative The centrioles of centrosomes duplicate during S-phase The centrioles of centrosomes duplicate during S-phase Structure of the Mitotic Spindle SUMMARY OF DNA REPLICATION
Origin Recognition Complex proteins are always bound to origin of replication DNA
Cdc6 made transiently in G1
Binding of cdc6 and MCMs to ORC makes pre-RC (ready to fire)
MCMs = DNA helicase
Activation of S-Cdk triggers replication
S-Cdk phosphorylates cdc6 and causes its destruction by ubiquitination
ORC is also phosphorylated to inhibit cdc6 binding
Everything is reset after M-phase 1. Prophase Chromosome condensation is caused by Condensins The Nuclear Envelope is Dismantled at the end of Prophase and Reformed during Telophase 2. Prometaphase Prometaphase 1. Centrioles
Kinetochore MTs are formed because the nuclear envelope is completely degraded and kinetochores are exposed to chromosomes.
Kinetochore MTs capture the chromosomes adn move them to the metaphase plate via motors. (see picture) Alberts 17-30 KRP KRP chromokinesin Many Microtubule Motor Proteins work on the Spindle 3. Metaphase Metaphase Begins when all the chromosomes are lined up at the metaphase plate. The KRPs and dyenins on each side of the kinetochores are balanced out and stable. Karp 14-30 Balance of Forces at Metaphase Metaphase Checkpoint Checks that all chromosomes are lined up properly in the middle of the cell and bound to kinetochores.
Mad2 proteins are found on the kinetochores. Once the chromosome is bound to the kinetochore and aligned in the middle of the cell, Mad2 disappears.
APC/Cdc-20 - an E3 ligase complex, which ubiquitilates securin, which is an inhibitor of separase.
Active separase cleaves cohesins to allow sister chromatid separation. M-cyclin is degraded by APC/Cdc-20 complex, which ubiquitilates M-cyclin.
M-Cdk activity drops Anaphase Promoting Complex (APC) The APC/cdc20 complex is an E3 Ubiquitin Ligase Complex Degradation of M-Cyclin occurs by the Ubiquitin//Proteasome pathway and is mediated by the Active APC/Cdc20 Complex Alberts 17-20 Metaphase
Checkpoint 2. Kinesin Related Proteins
Can be plus or minus end directed motors
Found on kinetochores, binds to overlapping MTs from both centrosomes.
Creates an equal amount of force pushing and pulling the MTs to stabilize them. 4. Anaphase Anaphase A Anaphase B Occur simutaneously Anaphase A
Shortening of the kinetochore MT at the (+) end
This is done by depolarization of the kinetochore MT
As the MT is shrinking, the kinetochore has protein arms that attach and detach to the MT, allowing it to follow the depolarization of the MT Dynein on the Kinetochore also participates in Anaphase A Depolymerization of Kinetochore Microtubules from their (+) ends contribute to the movement of chromosomes during Anaphase A Anaphase B
PUSHING FORCE- Growing of overlapping MTs at the (+) end causes KRPs to push the poles apart
PULLING FORCE- Dyneins attached to the cell membrane bind to astral MTs and pull the centrosome to the poles "Minus-end-directed motor protein" = Dynein Anaphase B uses both Plus and Minus-end directed motors and Elongation of Overlap MTs Telophase
The decreasing level of M-cyclin allows the nuclear lamins to de-phosphorylate, recreating the nuclear envelope.
Condensins are also de-phosphorylated which allow the chromosomes to deconsense. Cytokinesis
Accomplished by the constriction of the acto-myosin contractile ring
Astral MTs control the placement of the ring 5. Telophase