L1 Cell Cycle Flashcards
A mixture of signals has to be integrated by the cell to make the decision to proliferate, be quiescent of differentiate
Existence of a master governor that makes major decision regarding cell fate = cell cycle clock, which operates in the nucleus
Cell cycle clock
Network of interacting proteins that receives signals from outside and inside the cell, integrates them and decides the cell’s fate
Proliferation
Proliferation -> cell cycle of growth and division
Quiescence
Quiescence -> non-proliferative state imposed on the cell
Interphase - G1 phase
- Cell increases in size
- Ribosomes, RNA produced
- Preparation for DNA synthesis
Interphase - S phase
- DNA synthesised (chromosome duplicated)
Interphase - G2 phase
- Cell checks fidelity of DNA
- Preparation for nuclear division
MITOSIS: cell division
Sub-phases: - prophase, prometaphase, metaphase, anaphase, telophase
- cytokinesis
Remember you have 2 major control factors
The normal control by different cyclins – this drives the cycle forward
Mechanisms to stop the cycle (and correct) if there are problems ie Checkpoints
R = restriction point
– Beyond this you no longer need eternal signals to drive the cell cycle
Pairing of cyclins with CDKs G1:
CDK4 and CDK6 depend on the association with cyclin Ds (D1,D2 &D3 = D-type cyclins)
Pairing of cyclins with CDKs
After the R point:
E-type cyclins associate with CDK2 -> phosphorylation of substrates required for entry in S phase
Pairing of cyclins with CDKs
S phase:
: A-type cyclins replace E cyclins in complex with CDK2 -> S phase progression. Later in S-phase, A-type cyclins associate with CDC2 (also called CDK1)
Pairing of cyclins with CDKs
G2:
B-type cyclins replace A-type ones in the complex with CDC2
Pairing of cyclins with CDKs
M phase:
B-type cyclins/CDK1(CDC2) -> mitosis triggering
Pairing of cyclins with CDKs
G0 to G1:
Mediated by cyclin C/CDK3 complex
Cyclin levels fluctuate during the cell cycle
Cyclin E:
Low levels throughout most of G1, rapid increase after the R point
Cyclin levels fluctuate during the cell cycle
Cyclin A:
Levels increase in concert with the entrance in S phase
Cyclin levels fluctuate during the cell cycle
Cyclin B:
Levels increase in anticipation of mitosis
Cyclin levels fluctuate during the cell cycle
Collapse of cyclin levels as the cell progresses through the cell cycle -> degradation (ubiquitination-dependent)
The cell cycle can only progress in one direction
Exception: D-type cyclins
D-type cyclins (D1 is the most studied) are controlled by extracellular signals: growth factors + integrin-mediated ECM attachment
Removal of GFs -> rapid collapse of cyclin D1 levels
D-type cyclins convey messages from the extracellular environment to the cell cycle clock in the nucleus
synthesised in the cytoplasm & transported in the nucleus
Control of cyclin levels during the cell cycle
- D-type cyclins -> extracellular signals
- Other cyclins -> intracellular signals & coordinated with cell cycle advance
cyclin/CDKs activate complexes of the subsequent phase & inhibit those active in the previous phase
Cyclin/CDKs are regulated by CDK inhibitors (CKIs)
CKI = CDK inhibitors -> 7 proteins antagonising the activity of cyclin/CDKs
Cell Cycle Checkpoints
G2 Checkpoint:
Is all DNA replicated?
Is cell big enough?
Is environment favourable?
Cell Cycle Checkpoints
Metaphase Checkpoint:
Are all chromosomes aligned on spindle?
Cell Cycle Checkpoints
G1 Checkpoint:
Is cell big enough?
Is environment favourable?
DNA damage?
G1/S restriction point progression
- Cyclin D has a high turnover its levels can only be maintained under continuous mitogen signalling
- As levels of CyclinD/CDK4 are maintained -> Rb is phosphorylated (actually HYPO phosphorylated).
- This allows some E2F transcription. E2F causes CyclinE/CDK2 to accumulate and this HYPER phosphorylates Rb to fully release E2F transcription and enter S-phase
There are 3 places where DNA damage is detected and acted upon to STOP the cell cycle
(i) G1
(ii) Entry to S-phase
(iii) Entry into mitosis
What happens if the DNA gets damaged?
+ check for chromosome non-disjunction
G1 repair = non-homologous end joining
G2 repair = homologous recombination
DNA Damage
- ATM/ATR get activated and associate with the site of DNA damage
- ATM/ATR will activate other kinases to block the cell cycle
- p53 is stabilised and turns on p21, (p21 is a CKI)
DNA Damage response in G1
- p21 renders the G1/S-CDK and S-CDK complexes INACTIVE. Thus preventing cycle progression
- DNA is then repaired
What happens if repair is not possible?
- Apoptosis
G1: growth v/s quiescence decision
Discrete window to consult the extracellular environment: from the onset of G1 phase to an hour or 2 before the G1-to-S transition.
G1 decision making machinery apparent in the responses of cultured cells to extracellular signals:
- Serum and growth factors removed before the cells have completed 80-90% of G1 -> fail to proceed further and revert to G0 state
- Serum and growth factors removed in the final hr of G1 -> proceed to S, G2 and M phase
- Restriction point (R point)
S-phase: The cell’s problems
- It has to copy very large arrays of DNA ie chromosomes and repackage the DNA for the next G1 phase
- S-phase is the central event where DNA is replicated.
Two problems - The DNA has to be replicated accurately to prevent mutations
- The DNA must only be copied ONCE
G1
- INACTIVE Helicases are loaded onto replication origins, forming a PreRC (pre-replication complex)
- This is called licensing
S
DNA is unwound.
DNA is replicated (forks move away from each other)
M
M-CDK trigger chromosome segregation
If the forks stall you can also get a DNA damage response.
- This can occur, for example when nucleotides are depleted in a cell.
- This response prevents cells segregating partially replicated chromosomes
[ You can also get DNA repair in S-phase where a mistake is detected and the DNA around it is resected and filled back in ]
