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Foundations 1 > Cell Cycle > Flashcards

Cell Cycle Flashcards

1
Q

What are the phases of the cell cycle?

A

G0, G1, S, G2, M

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2
Q

What happens in G1 phase?

A

Cell growth and preparation for DNA synthesis

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3
Q

What happens in S phase?

A

DNA synthesis

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4
Q

What happens in G2 phase?

A

Cell growth and preparation for mitosis

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5
Q

What happens in M phase?

A

Mitosis

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6
Q

What are cyclins and CDKs and how do they work together?

A
  • Cyclin = protein expression oscillates over cell cycle
  • Cyclin dependent kinase = stable expression
  • Cyclin proteins bind to cyclin dependent kinases
  • Each have low activity individually, but when bound CDK will phosphorylate
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7
Q

What cyclin-Cdk combos are present in G1?

A

Cdk4-cyclin D and Cdk6-cyclinD

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8
Q

What cyclin-Cdk combo is present in S and G2?

A

Cdk2-cyclin A

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9
Q

What cyclin-Cdk combo helps with the G1/S transition?

A

Cdk2-cyclin E

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10
Q

What cyclin-Cdk combo is present in G2 and M?

A

Cdk1-cyclin B

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11
Q

How is CDK/Cyclin activity regulated?

A

Availability of corresponding proteins:

  • regulated expression of cyclin genes
  • regulated degradation of cyclin genes

Activity of complex depends on:

  • CKI activity
  • Inhibitory/activating phosphorylations of Cdk/cyclin
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12
Q

Describe the temporal expression of cyclin and Cdk genes.

A

Cdk = constant

Cyclin = oscillates across different phases of the cell cycle

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13
Q

What is the pathway for the cyclic degradation of cyclins?

A

For M-cyclin, APC/C (an E3 ubiquitin ligase) controls proteolysis. Other cyclins have other E3 ligases (F-box proteins):

  1. Activation of APC/C:
    - Cdc20 activating subunit binds inactive APC/C
  2. Ubiquitylation of cyclin:
    - E1, E2, and APC/C ubiquitylate the cyclin
    - polyubiquitin chain is added to K residue
  3. Degradation in proteasome
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14
Q

What determines cyclin stability?

A

Cyclin ubiquitylation

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15
Q

How are inhibitory and activating phosphorylation involved in cell cycle progression?

A
  1. Cyclin and Cdk bind, forming an inactive complex
  2. Protein complexes add inhibitory and activating phosphates
    - Inhibitory phosphate trumps activating
  3. Activating protein phosphatase removes the inhibitory phosphatase
  4. Active cyclin-Cdk complex
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16
Q

What are the 4 mechanisms of Cdk activity regulation?

A
  1. Availability of cyclins
  2. Activating phosphorylation
  3. Inhibitory phosphorylation
  4. Association with Cdk Inhibitors (CKIs)
17
Q

How does cyclin activation progress through the cell cycle?

A

S: Cyclin A-Cdk2
G2: Cyclin A-Cdk1, cyclin B-Cdk1
M:
G1: Cyclin D-Cdk4, cyclin D-Cdk6, cyclin E-Cdk2

18
Q

What is a CKI?

A

Cyclin inhibitor protein: inhibits the active cyclin-Cdk complex (ex: p27)

19
Q

How (temporally and mechanistically) is CKI proteolysis regulated?

A

Cyclically regulated through the ubiquitylation pathway

  1. CKI phosphorylated by a kinase
  2. Active SCF (F-box protein) complex (an E3 ubiquitin ligase) controls proteolysis: ubiquitylation of CKI by E1-E3.
  3. Degradation in proteasome
20
Q

What Cdk-cyclin complexes are inhibited by the INK4 family of CKIs?

A

G1 phase: Cdk2,6-cyclinD

21
Q

What Cdk-cyclin complexes are inhibited by the CIP/KIP family of CKIs?

A

G1 phase: Cdk2-cyclin E
S phase: Cdk2-cyclin A
G2 phase: Cdk2-cyclin A
M phase: Cdk1-cyclin B

22
Q

Where in the cell cycle are the checkpoints? What is necessary to pass the checkpoint?

A

G1 checkpoint (major checkpoint) requires:

  • cell size
  • nutrient availability
  • growth factors present
  • no DNA damage

S phase: check for DNA damage

G2 checkpoint requires:

  • cell size
  • successful chromosome replication (no DNA damage or unreplicated DNA)

Metaphase checkpoint requires:
- all chromosomes attached to mitotic spindle

23
Q

What are the downstream mechanisms by which cyclin-Cdk activity determine cell cycle position?

A
  • Change gene expression and activate cell cycle stage specific transcription
  • Modify activity of existing proteins, exerting direct control over cell cycle specific processes
24
Q

What signals regulate exit from G0 and entry into the cell cycle?

A
  • Growth signals (+ or -) from nearby cells
  • TGFB signalling pathway
  • Differentiaiton signals
  • Cell-cell ECM contacts
  • DNA damage
25
Q

What are mitogens?

A

Growth factors

26
Q

How do mitogens stimulate cell division?

A

Mitogens activate cyclins:

  1. Mitogen binds cell surface mitogen receptor
  2. Cytosolic signaling cascade involving Ras and MAP kinase
  3. Immediate activation of gene expression and delayed-response gene expression (via Myc regulatory protein)
    - Increased synthesis of cyclin D and E2F
    - Increased p27 degradation
  4. Cyclins phosphorylate and inactivate Rb, activating E2F:
    - active Rb keeps chromatin compact and represses transcription
    - active G1-cdk complex phosphorylates and inactives Rb protein, freeing gene expression
  5. E2F activates all S-phase genes:
    - E2F, Cdk2, cyclinE, DNA replication factors, CyclinA
27
Q

How do mitogen levels impact cyclins D and E, specifically?

A

Low mitogen: CKIs bind cyclins D and E

High mitogen:

  • increased cyclin D expression
  • cyclin D binds more CKIs
  • freed cyclin E signals cell cycle progression
28
Q

How does positive feedback control S phase initiation?

A
  • Active E2F induces S-phase gene transcription, which increases E2F activity
  • Active G1/S and S cyclins (E and A) increase E2F activity
  • Active S-cdk increases E2F activity
29
Q

What is replication licensing?

A

Limitation of the activation of the origins of replication to once per cell cycle to avoid re-replicating DNA

30
Q

What is the mechanism of replication licensing?

A

G1:
- Cdc6 and Cdt1 proteins bind ORC, inhibiting helicase and thus replication

S:

  • S-Cdk phosphorylates Cdc6, which releases from the pre-RC and is degraded
  • Cdt1 is inhibited from geminin, releasing it from the pre-RC
  • Preinitiation complex binds to the ORC and ORC is phosphorylated
  • DNA replication

G2/M:
- ORC remains phosphorylated, preventing re-binding of Cdc6 and Cdt1

31
Q

How does the G1/S checkpoint halt/restart the cell cycle to allow for DNA repair?

A
  1. DNA damage activates a kinase signaling cascade (ATM/ATR -> Chk1/Chk2)
  2. Kinases phosphorylate p53, releasing it from Mdm2 and activating it.
  3. Stable, active, phosphorylated p53 binds to regulatory region of p21 gene
  4. p21 (cyclin inhibitor) binds G1/Cdk (cyclinE/Cdk2) and S-Cdk (cyclinA)
  5. Cell cycle is inhibited during DNA repair
32
Q

How is the cell cycle regulated during mitosis?

A

Replication forks suppress mitosis during DNA replication

33
Q

What proteins mediate the G2/M DNA damage checkpoint?

A

ATM/ATR and DNA-PK -> p53, among others….

34
Q

What is cellular senescence? What induces it?

A

Permanent cell cycle arrest to remove potentially damaged cells from the cell population.

Induced by DNA damage, mitochondrial dysfunction, aneuploidy, telomere attrition, oxidative stress

35
Q

What is quiescence? What induces and reinforces it?

A

G0 = temporary removal of normal cells from the cell cycle

Induced by low mitogen and/or nutrients, contact inhibition

Reinforced by CKIs:

  • INK4 binds cyclinD-Cdk4,6
  • KIP1 inhibits cyclinE-Cdk2
  • Cyclin D levels are reduced
  • Rb is hypophosphorylated and bound to E2F

To escape: high levels of mitogen => increased cyclin D => outcompete INK and can bind p27-KIP, freeing cyclinE to resume the cell cycle

36
Q

What proteins are involved in senescence?

A

Various upstream causes activate p53, p21, p16

These proteins inhibit cyclin-Cdks

Rb is kept active, maintainign senescence

37
Q

What are telomeres?

A

ss ends of chromosomes that shorten with each replication due to the nature of replication (okazaki fragments)

38
Q

What is the Hayflicks limit?

A

A limit to cellular replication caused by shortened telomeres => replicative senescence.

39
Q

How can cells avoid telomere crisis?

A

If p53 is inactivated, normal p53 mediated senescence will not occur:

  1. Activation of salvage and NHEJ pathways -> breakage fusion cycles
  2. Telomerase is re-expressed, allowing for extension of telomeres

Foundations 1 (26 decks)

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