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4 CAN > 10 The maintenance of genomic integrity > Flashcards

10 The maintenance of genomic integrity Flashcards

1
Q

What are the 5 major types of DNA repair?

A

Direct reversal of damage

Base excision

Nucleotide excision repair

Homolgous recombination repair and non-homologous end joining

DNA mismatch repair

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2
Q

name 2 common types of DNA damage

A

7-methyl-guanine (methylation)

G-C -> A-T

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3
Q

What causes G-C -> A-T?

A

drug ethyl methane sulphonate

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4
Q

How does G-C -> A-T work?

A

G pairs with C
O*6 alkyl G pairs with T
T pairs with A

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5
Q

What does 7-methyl-guanine cause?

A

large DNA distortions, DNA replication issues, cell lysis

this might be ok if the overall dose if not too bad

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6
Q

What does the O6 alkyl guanine mutation cause?

A

not death but mutagenic

still dangerous

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7
Q

What are the major forms of damage induced by sunshine UV light?

A 
thymine dimers (CPD)
(6-4) photoproducts
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8
Q

What do thymine dimers form?

A

cyclobutane rings

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9
Q

How might you split DNA repair into 2 groups?

A

enzymatic reversal

removal and replacement of damage

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10
Q

What are the 3 subtrates of BER?

A

spontaneous hydrolytic depurination of DNA

deamination of cytosine

Formation of DNA adducts after exposure to reactive small metabolites

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11
Q

What is the process of BER?

A

altered DNA base excised by DNA glycosylase
abasic site corrected by concerted action of …

apurinic endonuclease
DNA polymerase
DNA ligase

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12
Q

What are the 4 steps to removal and replacement of DNA damage?

A

removal of base
removal of apurinic site
addition of new nucleotides
ligation

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13
Q

What is NER?

A

nucleotide excision repair

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14
Q

Does NER target ssDNA or dsDNA?

A

dsDNA

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15
Q

Is NER specific or general?

A

general, it targets distortions in DNA, rather than specific adducts

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16
Q

What is the principle of NER?

A

endonuclease
Exonuclease
Polymerase
Ligase

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17
Q

Which of BER and NER acts on a larger scale?

A

NER

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18
Q

What is the principle of daughter strand gap repair in NER?

A

dimers remain after ‘repair’
this is really a tolerance mechanism
dimers are removed later from the dsDNA by excision repair

19
Q

How is Xeroderma Pigmentosum inherited?

A

Autosomal Recessive

20
Q

What is Xeroderma Pigmentosum characterised by?

A

extreme sun sensitivity

sometimes a neurological abnormality

21
Q

What defect is present in those with XP?

A

in excision deficient XP patients there is a failure to excise the damage
thymine dimer remains in situ

22
Q

How many forms of XP are there?

A

8

23
Q

How is NER used to correct daughter strand defects in XP?

A

XPC recognises dimer (help from XPE)
binds to site
allows recruitment of tf2H complex
together with XPA they come to dimer site

DNA unwinds
2 more proteins come and snip it either side of dimer (XPF + XPG)
these bases are replaced by polymerase

24
Q

Mutations in what gene are associated with basal cell Naevus syndrome?

A

PTCH1

25
Q

What proportion of BCCs from XP patients have PTCH1 mutations?

A

73%

26
Q

Name 4 key XP variants

A

not NER deficient

not sensitive to killing UV

DNA replication defect following UV exposure

DNA polymerase deficiency

27
Q

What is the principle of XP which is not sensitive to kiling UV?

A

cells are still hypermutable by UV

sensitivity to UV can be enhanved by caffeine

28
Q

What is the principle behind XP DNA polymerase deficiency

A

hRad30
able to replicate DNA past UV photoproducts
translation synthesis

29
Q

What do you have to look out for with repair of dsDNA breaks?

A

caused by errors in replication

caused by metabolic problems like ROS

30
Q

What 2 processes are involved in repairing dsDNA breaks?

A

non-homologous end joining

homologous recombination repair

31
Q

How is strand exchange initiated in homologous recombination repair?

A

Rad51 coats ssDNA to form nucleoprotein filament
invades and pairs with homologous DNA duplex
initiates strand exchange

32
Q

How is BRCA1 involved in HRR?

A

removes 53BP1 at DSg sites prior to reception and recombination

33
Q

How do BRCA2 mutations affect Rad51 interactions?

A

block relocalisation of Rad51

34
Q

What are the key features of non-homologous end joining?

A

Rad51 independent
BRCA2 not required for DNA DS8 by NHEJ
V(D)J recombination is normal in BRCA deficient mice

35
Q

What is non-homologous end joining used for?

A

formation of BCR and TCR

V(D)J recombination

36
Q

How is sensitivity to poly ADP ribose polymerase (PARP) inhibitors affected by cells being defective in homologous repair?

A

increased sensitivity

37
Q

For which sorts of tumours are PARP inhibitors really important for treating?

A

tumours with recombination repair deficiencies (like ovarian cancer)

38
Q

What happens if you inhibit PARP1?

A

replicaiton fork reaches it and it becomes a ds break:(

cell death rip
treating tumours with BRCA1/2 with a PARP inhibitor makes the defect worse

39
Q

What is the principle of DAN mismatch repair?

A

repair copy errors made during DNA replication

40
Q

What is HNPCC?

A

hereditary non polyposis colorectal cancer

41
Q

What do mismatch repair genes normally do?

A

repair base-base mismatches

repair insertion deletion loops which arise as a consequence of polymerase ‘slippage’ during replication

42
Q

What is the genetic basis of HNPCC?

A

mutation in mismatch repair gene
unrepaired MS called microsatellite instability (MSI)
genes that have microsatellites in their coding region have an increased risk of mutation in HNPCC

43
Q

What did the mutator phenotype hypothesis originate from?

A

microsatellite instability
difficulty in mismatch repair will cause mutation

with each round of replication, you will accumulate mutations

44
Q

What does the mutator phenotype hypothesis suggest?

A

mismatch repair defects lead
to mutations in other genes

increased mutation rate causes accelerated tumourigenesis

4 CAN (21 decks)

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