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PHAM02 > DNA damage and repair > Flashcards

DNA damage and repair Flashcards

1
Q

spontaneous deamination of DNA

A

at 37 degC, spontaneous deamination of C, A and G bases in DNA

C deaminates to form U
A to hypoxanthine
G to xanthine

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2
Q

What does C deaminate to?

A

U

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3
Q

What does A deaminate to?

A

hypoxanthaine

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4
Q

What does G deaminate to?

A

xanthine

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5
Q

What happens during spontaneous depurination?

A

cleavage of the glycosol bond connecting purines to the backbone

leaves the backbone of DNA intact

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6
Q

What are depurinated sites called?

A

abasic (lacking a base)

or

AP sites

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7
Q

What are APsites?

A

depurinated sites

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8
Q

What forms from hydroxyl radical and G?

A

8-oxoguanine

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9
Q

What does 8-oxoguanine do?

A

mutagenic

it pairs with A not C in DNA replication

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10
Q

What can replication stress give rise to?

A

DNA singlestrand breaks SSB

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11
Q

What can SSBs give rise to?

A

souble strand breaks DSB

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12
Q

2 types of mutations

A
  1. point mutations - single AA change
  2. frameshift mutation - insertion/deletion of bases
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13
Q

types of point mutations

A
  1. silent - has no effect on AA sequence
  2. missense - new AA substitution
  3. nonsense - stop codon for an AA
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14
Q

types of frameshift mutations

A

deletion - change in AA dequence

insertion - change in AA sequence

-> frameshift - multiple changes in AA

-> non-frameshift - insertion of single AA

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15
Q

what does gene amplification produce

A

multiple copies of the gene

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16
Q

what does gene deletion result in

A

reduced/loss of protein function

hemizygous - loss of 1 copy

homozygous - loss of both copies

17
Q

example of gene amplification

A

HER2 amplificaiton in breast cancer

18
Q

example of gene deletion

A

PTEN in prostate cancer

19
Q

What can DNA damage be?

A
  • misincorporation of a single base
  • chemical modification of bases
  • chemical cross-links between the 2 strands of the double helix
  • breaks in 1/both of the phosphodiester backbonoes
20
Q

What thing can correct DNA mismatches during replication?

A

DNA polymerase

21
Q

what can happen at exonuclease

A

the polynucleotide chain can leave polymerase site, go to active site of exonuclease

here, nucleotides can be removed, removing any incorrect bases

22
Q

5 DNA repair mechanisms

A
  1. BER: base excision repair
  2. NER: nucleotide excision repair
  3. MMR: mis-match repair
  4. NHEJ: non-homologous end joining
  5. HR: homologous recombination
23
Q

How does BER work?

A

BER used to correct damaged DNA bases or single strand DNA breaks

DNA glycolase excises faulty base

2nd strand used as a template

DNA polymerase fills in DNA gaps

DNA ligase seals the DNA

no defects to BER are inherited

24
Q

important protein in BER

A

PARP

25
Q

NER

A

acts on variety of helix-distorting DNA lesions

important in the response to adduct forming chemo agents (Pt based)

removal of damage such as pyrimidine dimers - UV light

26
Q

important protein in NER

A

XPA
XPC

27
Q

inherited disorders from NER

A

XP - xeroderma pigmentosum

autosomal recessive inherited condition

mutations in XP genes - XPA, XPC

sensitivity to sunlight - inc skin cancers

neurological impairment

28
Q

problems with xeroderma pigmentosum

A

sensitivity to sunlight

neurological impairment

29
Q

similarities in BER and NER

A

DNA polymerase fills gap

DNA ligase seals nick

30
Q

MMR - mismatch repair

A

catches damage not repaired by BER/NER

removes mis-paired nucleotides that result from replication errors

consist of at least 2 proteins
- 1 to detect the mismatch
- other for recruiting endonuclease that cleaves the newly synthesised DNA

repair of DNA adducts from Pt chemo agents

31
Q

important protein in MMR

A

MLH1

32
Q

NHEJ - non homologous end joining

A

double strand breaks critical - cell must repair asap

ATM halts cell cycle - checkpoint

rapid repair mechanism

repairs 85% of DNA damage from ionising radiation

operates at ALL stages of cell cycle

BUT IS ERROR PRONE

33
Q

important protein in NHEJ

A

ATM

34
Q

inherited condition with NHEJ

A

ATM - ataxia telangiectasia mutated gene

autosomal recessive inherited condition

neurological condition

ataxia = lack of order, poor coordination

telangiectasia - dilated/spider blood vessels (eye)

mutations in ATM

severe sensitivity to ionising radiation

20% incidence in developing cancers

immunodeficiency - higher levels of infection

mean age of death = 25yrs (1/3 cancer, 1/3 chronic lung disease)

35
Q

HRR - homologous recombination repair

A

ERROR FREE

only works in S and G2 phases of cell cycle

needs sister chromstids present

ATM
BRCA1, BRCA2

36
Q

What inheritence are BRCA mutations?

A

autosomal dominant inherited condition

37
Q

synthetic lethality

A
  • normal cells can rely on BRCA2 and PARP for DNA repair
  • BRCA BC are addicted to PARP (BER)
  • BRCA BC are sensitive to PARP inhibition

-> give PARP inhibitors for BC

PHAM02 (32 decks)

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