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FOM - WLB > Week 5 Holy - Cell Cycle > Flashcards

Week 5 Holy - Cell Cycle Flashcards

1
Q

What proteins are responsible for driving the cell cycle?

A
  • Cohesins
    • keep replicated chroms together until it is appropriate to separate them
  • Condensins
    • involved in chromosome condensation
    • help pull chroms apart
  • Centromeric heterochromatin?
  • Spindle architecture?
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2
Q

How is S-phase triggered?

A

S-Cdk: Cyclin A, CDK 2 or 1

  • CDK 2 recruits preinitiation complex proteins to the origin of replication complex (ORC)
    • unwinds DNA helix
    • loads necessary replication enzymes
  • S-Cdk phosphorylates pre-RC proteins, realeasing and destroying them
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3
Q

What are the two primary ways CDK activity is regulated?

A
  • presence of cyclin
  • specific pattern of Cdk phosphorylation
    • Cdk Inhibitors (CKIs)
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4
Q

What are CkIs?

A

Cdk Inhibitors

Proteins that bind to the cyclin-Cdk complexes and block the kinase activity of the Cdk.

(also arrest the cell cycle if G1or S if unfavorable conditions)

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5
Q

What is interphase?

A
  • G1, S-phase, and G2
  • period when newly divided cells grow to their “adult” size
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6
Q

What is the M-phase?

A
  • Mitosis phase
    • accurate segregation of duplicated chromosomes into two complete genomes
  • Cytokinesis
    • pinching of the cell into two daughter cells
  • about 1 hour long
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7
Q

What is G1?

A
  • Phase directly after M-phase
  • Decide whether to remain cycling, or stop dividing (enter G0).
  • Restriction point (R) or Start = cell is committed to initiating DNA synthesis and entering mitosis.
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8
Q

What is S-phase?

A
  • The period of the cell cycle when DNA synthesis occurs
    • chroms replicate
    • centrosome replicates
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9
Q

What is G2?

A
  • The period between the completion of DNA synthesis and the onset of M-phase
    • chroms begin to condense
    • merges into M-phase
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10
Q

When do cohesins release chromatids and allow them to be accurately separated?

A

When spindle apparatus binds in the M-phase

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11
Q

What do condensins do?

A

Allow chroms to be separated in a more manageable fashion.

They may form ring-like structures that encircle loops of DNA.

(mechanisms are not well understood)

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12
Q

How is DNA replication triggered in S-phase?

A
  • pre-replicative complex binds when unphosphorylated
    • provides substrates for Cdks
  • activation of S-Cdk (2or1) → recruits more proteins to form pre-initiation complex
    • unwinds DNA → REPLICATION!
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13
Q

How is G1 regulated?

A
  • Growth factors bind to their receptors
    • generally tyrosine kinases
  • Ligand binding activates Ras g-protein which → activates MAP kinase cascade
  • activated MAP kinase is transported into nucleus and activates transcription factors (phosphorylates them)
  • produce cyclin D and either Cdk 4 or 6
    • phosphorylates Rb → Rb releases active E2F
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14
Q

How are positive feedback loops used cell cycle regulation?

A
  • S-Cdk (cyclin A, Cdk 2 or 1) positively regulates the G1regulation
    • helps keep Rb inactivated (by phosphorylation) to provide active E2F
  • S-phase gene transcription positively regulates active E2F protein
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15
Q

What are ORCs?

A

Origin Replication Complexes

  • where DNA replication begins
  • multiple locations along each chromosome
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16
Q

What are pre-RCs?

A
  • Pre-Replication complex
  • complex of initiator proteins that assemble on ORCs​
    • substrates for Cdks
    • only bound when unphosphorylated
    • ex. Cdc6, Cdt1, Mcm helicases
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17
Q

Why is overal Cdk activity very low in early G1?

A

At the end of mitosis and early G1, all Cdk is inactive due to cyclin destruction by anaphase-promoting complex (APC) (allows binding of pre-RC proteins to ORC in early G1).

AND

Because Cdk has to wait to be activated until after all of the building materials for DNA replication are made during in G1.

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18
Q

Approximately how long is the entire cell cycle?

A

24 hours

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19
Q

Approximately how long is S-phase in a typical mammalian cell?

A

8-12 hours

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20
Q

Approximately how long is M-phase?

A

1 hour

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21
Q

What is the purpose of the kinetochore?

A

Interact with microtubules of the spindle apparatus so that daughter chromatids can be separated.

(also have signaling functions in the metaphase checkpoint)

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22
Q

What is centromeric heterochromatin?

A

Centromeres of chroms that contain special histone H3 variants that have tightly compacted chromatin (heterochromatin).

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23
Q

During what phase does the centrosome of the cell replicate?

A

S-phase

24
Q

How do microtubules move chroms away from the poles in metaphase and separate chroms in anaphase?

A

Mixture of pushing/pulling forces!

  • Microtubule polymerization and depolymerization
  • interaction of microtubules with actin/myosin
  • activities of dynein (-) and kinesins (+)
25
Q

What happens during Anaphase A?

A

chroms move toward poles

shortening of kinetochore microtubules via microtubule depolymerization

26
Q

What happens during Anaphase B?

A

Spindle poles move farther apart

(achieved through interaction of interpolar and astral microtubules with motor proteins)

27
Q

How does the small G-protein Rho help in Cytokinesis?

A

Organizes actin and myosin into a contractile ring, which constricts, forming a cleavage furrow and pinching the cell into two.

28
Q

In order to become inactive, M-Cdk (CAK) requires a phosphate group in its inhibitory site, which it receives from what Cdk inhibiting kinase?

A

Wee1

29
Q

In order to become active, M-Cdk (CAK) has a phosphate group removed from its inhibitory site by what phosphatase?

A

Cdc25

30
Q

What is terminal differentiation?

A

when cells irreversibly enter G0

(neurons and skeletal muscle cells do not divide)

31
Q

What is EGF? What does it stimulate?

A

Epidermal Growth Factor

  • molecule secreted to reactivate the cell cycle
  • stimulate exit from G0 and a re-entry into G1
32
Q

What role does E2F have in the transition from G1to S-phase?

A

E2F turns on genes encoding proteins necessary for S-phase initiation.

Active E2F also promotes transcription of its own gene (positive feedback loop).

33
Q

When are origins of replication “licensed” (rendered competent for replication?

A

Early in G1 when pre-RC proteins are unphosphorylated and can bind due to overall low Cdk activity.

34
Q

What things is M-Cdk responsible for in M-phase?

A
  1. chromosome condensation
  2. nuclear envelope breakdown
  3. mitotic spindle formation
  4. fragmentation of the Golgi apparatus and ER
35
Q

When is M-Cdk activity at its highest?

A

METAPHASE

corresponds to the peak of M-Cdk activity

36
Q

How is M-Cdk activity regulated?

A
  • M-cyclin (cyclin B) increased during G2 and M-phase via increased transcription.
  • Cyclin B + Cdk 1 = M-Cdk
  • Phosphorylated by:
    • inhibitory kinase (Wee1) → low activity
    • activating kinase (CAK/Cdc25) → increases activity
      • Active M-Cdk positively feedbacks to activate more Cdc25
      • Active M-Cdk inhibits Wee1 in another positive feedback loop
37
Q

What are the targets of M-Cdk?

A
  • Condensins
  • Centrosomal proteins
  • Nuclear pore complexes
  • Lamins
  • Proteins involved with fragmentation of Golgi and ER
  • APC (Anaphase-promoting complex)
38
Q

Phosphorylation and triggering of the anaphase-promoting complex (APC) by M-Cdk activates its function as a what?

A

Ubiquitin ligase

-APC targets are ubiquinated and subsequently recognized and destroyed by proteasomes

39
Q

APC targets include what two things?

A
  • Securins
    • protein that inhibits separase (proteolyses cohesins)
    • leads to the separation of sister chromatids
    • inhibiting an inhibitor
  • Cyclin
    • destruction of the cyclins brings all Cdk activity to a halt
    • reversal of phosphorylation state of Cdk target proteins
40
Q

What events in M-phase does M-Cdk induce?

A

First half of Mitosis:

Prophase, Prometaphase, and Metaphase

(also catalyzes its own destruction by activating APC)

41
Q

What events in M-phase does anaphase-promoting complex (APC) induce?

A

Anaphase and Telophase

42
Q

What is the cell’s usual response to DNA damage?

A

First arrest the cell to allow for DNA repair to occur. Then re-activation of the cycle.

43
Q

If DNA damage is unable to be repaired, what happens to the cell?

A

Permanently exit cell cycle to G0(senescence arrest)

OR

Activation of the cell suicide pathway (apoptosis)

44
Q

What does the cell evaluate at the G1 checkpoint?

A

Favorable environment to enter S-phase?

DNA damaged after M-phase?

45
Q

What does the cell evaluate at the G2/M Checkpoint?

A

Is all DNA replicated?

Is DNA undamaged?

Environment favorable for mitosis?

46
Q

What does the cell evaluate at the M-phase Checkpoint?

A

Are all chromosomes attached to the spindle?

47
Q

When does p53 produce a cellular response to DNA damage?

A
  1. START in late G1 (primary response)
  2. G2/M-phase transition
48
Q

How does p53 respond to DNA damage?

A
  • serves as a transcription factor to induce the expression of CKIs
    • arrest the cell cycle to allow DNA repair to be attempted
  • can also trigger cell death if damage is too extensive for repair
    • activate gene encoding pro-death protein BAX
    • reduces chances of malignant transformation
49
Q

How is p53 activated in response to DNA damage?

A
  • indirect activation:
  • DNA damage → activation of ATM & ATR kinases
  • ATM/ATR phosphorylates & activates Checkpoint Kinases 1 & 2
  • Chk 1 & 2 phosphorylate p53 → reduced affinity for Mdm2
    • Mdm2 usually destroys p53
    • inhibition of an inhibitor
  • increased p53 → transcription of CKIs (p21)
  • CKIs arrest cell cycle → allow DNA repair
    • If unsuccessful → p53 promotes cell death
50
Q

How is the cell cycle arrested during G2?

A
  • ATM/ATR & Chk1/Chk2 kinases are activated
    • phosphorylate and inhibit Cdc25 phosphatase → no active M-Cdk
    • arrest cell at G2/M transition
51
Q

What kinase is present in kinetochores and is active in the abscence of attached microtubules?

A

Bub1

  • Active Bub1 inhibits the initiation of cohesin proteolysis, thus inhibiting anaphase onset
52
Q

Define oncogenes.

A

Genes which encode products that function in a positive way to promote tumorgenesis.

(mutations that generate oncogenes are gain-of-function)

I.e. gas pedal

53
Q

Define tumor suppressor.

A

Genes that encode proteins that are negative regulators of cell growth.

(mutations involving these genes that lead to uncontrolled cell growth are loss-of-function)

i.e. cell cycle “brake pedal”

54
Q

What are four tumor suppressor genes discussed in class?

A
  • pRB
  • p53
  • ATM/ATR
  • Chk1/Chk2
55
Q
A

FOM - WLB (20 decks)

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