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BMS247 - Stem cells > Checkpoint controls I > Flashcards

Checkpoint controls I Flashcards

1
Q

What is growth and division regulated by?

A

Progression through the cell cycle

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2
Q

What does the genetic material of 2 daughter cells depend upon?

What do defects in these cause?

A

The PRECISE execution of 2 processes:
1) Faithful REPLICATION of a cell’s genome in S phase

2) The proper ALLOCATION of the resulting duplicated DNAs to a daughter cell during M phase

Defects = cancer

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3
Q

What is the function of a checkpoint in the cell cycle?

A

Surveillance/monitoring mechanisms which monitor each step of cell cycle progression

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4
Q

When can/can’t cells progress through the cell cycle?

A

Can progress:
- ONLY if the pre-requisite step has been completed successfully

If not - cells cannot progress until the problems have been addressed

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5
Q

What happens if the problems which are causing the cell cycle to halt cannot be repaired?

A

The cell undergoes APOPTOSIS

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6
Q

Describe the G1/S phase checkpoint

A

Cell will not be permitted to enter S phase if the genome is in need of repair

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7
Q

Describe the intra-S phase checkpoint

A

DNA replication paused in response to DNA damage, allowing DNA to be repaired

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8
Q

Why can S phase increase in time?

A

Time taken for the DNA to undergo DNA repair (S phase pauses in response to DNA damage

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9
Q

Describe the G2/M checkpoint?

A

A cell will NOT proceed through this checkpoint until DNA REPLICATION has been completed

OR

There is DNA damage

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10
Q

Describe the spindle assembly checkpoint?

A

The metaphase/anaphase checkpoint:

  • Cell is not permitted to enter anaphase until all of the chromosomes are properly assembled on the mitotic spindle DURING METAPHASE
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11
Q

What happens if the chromosomes are incorrectly assembled on the mitotic spindle?

A

Daughter cells could have 2 different genomes

Leads to the ACCUMULATION of mutations that could lead to the formation of cancer

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12
Q

How do cancer cells behave differently to normal cells at checkpoints?

A

In normal cells, if there is DNA damage - the cells fail to progress through the cell cycle and don’t proliferate

In cancer cells - LOTS of DNA damage but STILL continue to PROLIFERATE

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13
Q

What mutations must occur in cancer cells so that they can go through the cell cycle?

A

INACTIVATION of one or more checkpoint controls

In addition to acquiring oncogenes and inactivated TSGs

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14
Q

What is the R point essential for?

A

At the end of G1 - in order for the cells to make a decision if to proliferate or become quiescent

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15
Q

What is pRb?

A

A nuclear PHOSPHOprotein that is ABSENT or in a DEFECTIVE form in many tumours

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16
Q

What is the molecular governor of the R point?

How?

A

Rb (Retinoblastoma protein)

  • pRb undergoes PHOSPHORYLATION at the SAME time as the advance of cells through the cell cycle
  • Hyperphosphorylation of pRb inactivates the protein and allows the advance through the cell cycle
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17
Q

What happens when pRb is active?

A

PREVENTS the cells from going through the R point and the rest of the cell cycle

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18
Q

When is pRb activate?

A

When pRb is unphosphorylated or hypophosphorylated

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19
Q

When is pRb inactive?

A

When INACTIVATED

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20
Q

What is pRb phosphorylation governed by?

A

The components of the cell cycle

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21
Q

When is pRb NOT phosphorylated?

A

In G0

22
Q

What happens to pRb in early/mid G1?

A

D-type cyclin and CDK4/6 initiate pRb phosphorylation

Causes HYPOPHOSPHOYLATION

23
Q

What is hypophosphoylation of pRb?

A

Only a SMALL number of residues are phosphorylated

24
Q

What is hyperphosphoylation of pRb?

A

Phosphorylation of a LARGER number of residues

25
Q

What mediates the hyperphosphorylation of pRb?

A

Increase of cyclin E increase a R-tpoint

Cyclin E/CDK2 mediates the hyperphosphorylation
Advancement through late G1

26
Q

What happens to pRb after early/mid G1?

A

pRb remains HYPERPHOSPHORYLATED for the remainder of the cell cycle

27
Q

When is pRb dephosphoylated?

What does this allow?

A

When the cells exit mitosis

Cell cycle can start again

28
Q

What does the E2F transcription factors do?

How?

A

Enables pRb to implement growth vs quiescent decisions:

  • UNphosphoylated or HYPOphosphorylated pRb bind E2F
  • HYPERphosphoylated pRb dissociates from E2F
29
Q

What happens with pRb and E2F in G1?

A

1) pRb is HYPOphosphorylated

2) pRb binds to E2F - preventing the transcription of E2F dependant genes

30
Q

What happens with pRb and E2F at the R point?

A

1) pRb is HYPERphosphorylated

2) E2F is RELEASED - transcription of the genes mediating G1/S transition

31
Q

What happens to pRb and E2F as the cells undergo G1/S transition?

Why?

A

Transcriptional activity of E2F is inhibited by Cyclin A/CDK2 which is formed at the G1/S transition

E2F is DEGRADED by UBIQUITINATION

32
Q

What is the length of action of the E2F transcription factor?

A

Short lived

33
Q

What are the positive feedback loops in pRb/E2F signalling?

A

1) pRb is HYPERphosphorylated by cyclin E/CDK2 –> ACTIVATION of E2F (released)

  • One of the target genes of E2F is cyclin E
  • Further INHIBITION of pRb
  • Further ACTIVATION of E2F

2) Cyclin E-CDK2 induces the PHOSPHORYLATION of p27^Kip1 (CKI), which is ubiquitinated and degraded
- More E-CDK2 released from inhibition

34
Q

What ensures the cell cycle is irreversible?

A

Positive feedback loops

35
Q

Describe the separation of the sister chromatids during anaphase?

A

IRREVERSIBLE step:

  • Cycle will not proceed until ALL the chromosomes are attached to at least 2 spindle fibres from the OPPOSITE poles
  • If chromosome miss placed - cell will pause mitosis, allowing time for the spindle to capture the stray chromosome
36
Q

What is the progression into anaphase controlled by?

How?

A

The anaphase promoting complex/cyclosome (APC/C):

1) The APC is activated when all the chromosomes are aligned
2) APC/C ubiquitinates SECURIN and causes it to undergo degradation
3) Causes the activation of separase

37
Q

What keeps the 2 sister chromatids together?

A

Cohesion

38
Q

When is separase inactivated?

A

Inactivated when in a complex with SECURIN

39
Q

When is separase activated?

What happens when separase is activated?

A

When securin is INACTIVATED

When separase is activated:
1) Breaks the link between the 2 chromatids by DEGRADING cohesion

2) Allowing anaphase to initiate and the sister chromatids to be pulled towards the opposite sides of the cell

40
Q

What 2 things are checked at the G2/M checkpoint?

A

1) DNA integrity (absence of damage)

2) DNA replication (DNA completely copied during S phase)

41
Q

What is the passage through the G2 checkpoint triggered by?

A

MPF (mitosis promoting factor)

42
Q

What is a MPF?

A

A cyclin B/CDC2 complex

43
Q

What happens is the checkpoint mechanism detects a problem with DNA (damage or incomplete replication)?

A
  • Cell cycle HALTED

- Cell attempts to either COMPLETE DNA replication or REPAIR damaged DNA

44
Q

What happens if the cell CAN repair the problem with DNA?

A

Cell can progress through mitosis

45
Q

What happens if the cell CAN’T repair the problem with DNA?

A

Cell may undergo APOPTOSIS

46
Q

What is DNA detected by?

A

The action of 2 kinases:
1) ATM

2) ATR

47
Q

What does ATM detect?

A

ds breaks in DNA

48
Q

What does ATR detect?

A

ss breaks in DNA

49
Q

What doe ATM and ATR do when they identify DNA breaks?

A

1) Phosphorylate downstream signalling
2) Activation of many downstream pathways
3) Leads to cell cycle arrest, activation of DNA repair and apoptosis (if repair not possible)

50
Q

Where do the signalling pathways of ATM and ATR converge?

A

On P53

51
Q

What is P53?

A
  • A TUMOUR SUPRESSOR that is lost or mutated in ~50% of ALL human tumours
  • TRANSCRIPTION FACTOR - promotes the expression of genes mediating growth-suppression, apoptosis and DNA repair
52
Q

What is the target gene of P53?

What does this do?

A

p21^Cip1 (a CKI)

Blocks the progression of cell cycle

BMS247 - Stem cells (15 decks)

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