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Cancer & The Cell Cycle > L4 - Early molecule events II > Flashcards

L4 - Early molecule events II Flashcards

1
Q

How is DNA damage repair integrated into the cell cycle?

A

Cells run safety check in G1 to look for damage

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2
Q

What are the three things a cell can decide to do after safety check?

A

Divide (enter S phase)
Arrest (pause to repair)
Apoptosis

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3
Q

What is usually mutated so that the safety check is compromised?

A

p53 ‘the gate keeper’

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4
Q

Features of p53

A
  • DNA binding domain into the major groove
  • Beta barrell
  • loop 2 positions loop 3 that has arginine 248
  • zinc finger
  • transcription factor
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5
Q

What does p53 do?

A

Increases p21^cip1 which causes cell cycle arrest

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6
Q

What does p21 inhibit?

A

Cyclin E and A/Cdk2 (prevents entry to S)
PCNA (halts DNA replication)
Possibly Ciz1

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7
Q

What is PCNA?

A

Multimeric ring structure, ‘sliding clamp’, accessory factor of DNAPol

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8
Q

What does PCNA do other than its role in DNA synthesis?

A

Attracts DNA repair factors to arrested DNA replication forks

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9
Q

What is selection inhibition?

A

p21 is able to inhibit DNA replication activity of PCNA but leave its repair activity intact

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10
Q

What a few things responders can do when told there is DNA damage?

A
  • stop txn
  • block cell cycle
  • change energy metabolism
  • repair
  • chromatin remodelling
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11
Q

What do the PIK family kinases do?

An example?

A

Recruited by partner proteins where they phosphorylate signalling proteins.
ATM (ataxia talengectasia mutated)

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12
Q

How do ATM end up inhibiting DNA synthesis?

A

NBS1 binds leading to Chk2.

Chk2 inhibits the phosphorylation of cdc25A so Cyclin E/A-Cdk2 is not phosphorylated and DNA synthesis is halted

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13
Q

What do ATM and ATR signalling do?

A

Inhibition of CDKs which arrests cell cycle at G1-S, intra-S or G2-M checkpoints.
Also activates repair enzymes by inducing their txn, recruiting them or modulating RNA processing

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14
Q

Why can homologous recombination only occur in S/G2?

A

Has to have a sister chromatid for the information to be copied from

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15
Q

What does ATM initiate?

A

Homologous recombination or non-homologous end joining

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16
Q

How does the cell choose whether to use HR or NHEJ?

A

By concentration of CDK.
In G1 cells CDK is low so goes through ATM to Chk2-p53-G1 arrest and to MRN-resection-NHEJ
In S/G2 cells CDK is high - leads to HR

17
Q

What is Chk2/

A

Serine/threonine kinase that transduces the signal from PIKs to decide if cell is arrested or not

18
Q

What happens to Chk2 when damage occurs?

A
  • Sits everywhere around chromatin
  • Phosphorylated by ATM causing Chk2 to homodimerise and autophosphorylate itself
  • Activated Chk2 can now phosphorylate other targets so responds quickly and spreads signal throughout nucleus
19
Q

What is Chk1 activated by and when is it activated?

A

Activated by ATR in response to replicative stress

20
Q

What was shown by staining of Chk2 in breast cancer?

A

Expression is lost in the tumour

21
Q

What was shown by staining phosphorylated Chk2 in breast cancer?

A

Normal cells - not much activation

Breast cancer - loads of activation

22
Q

What are BRCA1 and BRCA2?

A

Platform proteins with mutations found in 50% of breast cancers and 70% ovarian cancers
Support assembly of large multiprotein complexes involved in detection, signalling and attracting repair factors

23
Q

What is H2AX?

A

A histone who’s phosphorylation is mediated by ATM/ATR and is incorporated into chromatin at low frequency all over the genome

24
Q

What is H2AX used for and how?

A

To visualise the DNA damage repair.

  • UV light creates a stripe of damage on a cell
  • H2AX is phosphorylated locally at damage
  • Phosphorylated H2AX helps attracts repair factors
25
Q

What was shown by using H2AX?

A

BRCA1 was recruited to the strip of UV damage

26
Q

Who’s paper is referenced when answering ‘what drives the loss of repair functions?’

A

Bartkova et al 2005

27
Q

What did Bartkova show with one of their fluorescences?

A

Precursor lesions of breast, lung, colon and bladder cancers express markers of an activated DDR

28
Q

What was Bartkova’s hypothesis?

A
  • At an early stage incipient tumour cells experience ‘oncogenic stress’
  • respond to activating pathways (arrest or die)
  • mutations compromising pathways might allow proliferation
  • compromises checkpoints and increased genomic instability and tumour progression
  • chronic activation leads to deactivation and hyper mutation
29
Q

What can cause replication forks to slow down or stall?

A

inefficient DNA replication

30
Q

What can cause inefficient DNA replication?

A
  • disruption of nucleotide pools
  • DNA damage or protein obstructions
  • DNA secondary structure

Cancer & The Cell Cycle (8 decks)

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