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HDT 3.2 > Genome instability > Flashcards

Genome instability Flashcards

1
Q

why is genome instability considered a hallmark of cancer?

A

as genome instability becomes an enabling characteristic that drives/enhances genomic alterations/mutations

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2
Q

what are the types of gene damage?

A
  1. Intrinsic
    - Normal DNA replication
    - Spontaneous base damage
    - V(D) J recombination
  2. chemical agents
    - endogenous (oxygen radicals)
    -exogenous (chemical mutagens)
  3. radiation
    - ionising radiation
    - UV radiation
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3
Q

what types of DNA lesions does intrinsic gene damage cause?

A

base damage
base mismatches
insertions
deletions
DNA strand breaks

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4
Q

what types of DNA lesions does chemical agent gene damage cause?

A

Base modifications
Abasic sites
DNA adducts
DNA crosslinks
DNA strand breaks

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5
Q

what types of DNA lesions does radiation gene damage cause?

A

pyrimidine damage
Base modifications
Abasic sites
DNA stand breaks

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6
Q

what mechanism corrects DNA lesions

A

DNA damage response

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7
Q

what happens if DNA lesions aren’t corrected?

A

leads to genome instability

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8
Q

how do inherited mutations in DNA repair genes link to genome instability in cancer?

A
  1. genome instability present in precancerous lesions
  2. drives tumourigenesis by increasing mutation rate
  3. leads to mutations in oncogenes/tumour suppressor genes
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9
Q

what are the ways in which you can repair DNA lesions?

A
  1. base excision repair (BER)
  2. nucleotide excision repair (NER)
  3. mismatch repair (MMR)
  4. homologous recombination repair (HRR)
  5. non-homologous end joining (NHEJ)
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10
Q

what is single stand break repair?

A

responds to intrinsic - spontaneous base damage, chemical agents - exogenous (chemical mutagens)

to repair DNA lesions - base alkylation

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11
Q

what two types of enzymes repair base alkylation?

A

MGMT
ALKBH

both act directly on alkylated bases
with no steps

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12
Q

explain DNA repair pathways

A
  1. double stranded break (DSB) + abnormal DNA replication detected by the sensors
  2. signal reaches the transducer molecules
  3. activation of transducers
  4. recruit multi-functional mediator receptors
    4.5 amplification of effector protein recruitment to DNA w/ multiple lesions/breaks
  5. effector checkpoint
  6. DNA repair
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13
Q

what are some examples of sensors in DNA repair pathways?

A

MRN
or
RPA

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14
Q

what are some examples of transducers in DNA repair pathways?

A

ATM
or
ATR/ATRIP

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15
Q

what are some examples of mediators/adaptors in DNA repair pathways?

A

BRCA1/53BP1
or
TopBP1/claspin

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16
Q

what are some examples of amplifiers in DNA repair pathways?

17
Q

what are some examples of effectors in DNA repair pathways?

A

Chk2/p53
or
Chk1

18
Q

what do BER do?

A

remove simple alkylation and oxidative damage

repair DNA lesions from intrinsic factors:
base damage
abasic sites
DNA SSBs

19
Q

what do NER do?

A

removes bulky helix-distorting lesions (UV-C)

repair DNA lesions:
base modifications from chemical agents

20
Q

what do MMR?

A

removes mis-matched bases

repair DNA lesions: from gene translation

21
Q

How are DNA DSBs repaired?

A
  1. NHEJ - perform DNA DSB repair through the cell cycle
  2. HRR - requires homologous template for repair only in S/G2 of the cell cycle
22
Q

which pathway repairs DNA DSBs faster?

A

NHEJ - hours - faster due to simplicity
HRR - 8-24hours - slower

23
Q

what are the main ways of exploiting in genome instability in cancer treatment?

A
  1. loss of DDR pathway (genome instability)
  2. increased levels of replication
  3. increased levels of endogenous damage
24
Q

how are endogenous damage caused?

A

increase proliferation = increase metabolic pathways = increase endogenous damage

25
Q

what mutations can increase the risk of breast/ovarian cancer?

A

mutations in BRCA1/BRCA2

26
Q

how can mutations in BRCA1/BRCA2 be targeted?

A

PARP inhibitors

27
Q

when are PARP inhibitors used?

A

target tumours - prostate and leukaemia
BRCA1/BRCA2 in breast cancer

28
Q

how do PARPi target mutated BRCA1/BRCA2 ?

A

healthy cells : PARPi = DNA damage = BRCA1/BRCA2 repair DNA = cell survival

unhealthy cells: mutated BRCA1/BRCA2 = no DNA repair= cell death

29
Q

What pathway is BRCA1/BRCA2 apart of?

A

HRR repair for DNA DSBs

30
Q

how does PARPi break DNA?

A

collide and break up to replication forks = DNA DSB

31
Q

what are some PARPi drugs?

A

olaparib -ovarian/breast/pancreatic cancer

32
Q

what can BRCA1/BRC2 mutations cause?

A
  1. HRR deficiency
  2. sensitivity to platinum
34
Q

what else can PARPi be used with?

A

radiosensitsation

35
Q

what do most tumour cells have?

A

mutated ATM = no DNA repair
therefore rely mostly on ATR for DNA repair

36
Q

what is ATM?

A

regulates entire DNA repair

37
Q

what happens when you give ATRi drugs in tumours cells?

A

cell death as there’s no DNA repair

HDT 3.2 (17 decks)

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