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Genetics > L22 DNA Repair and Associated Disorders > Flashcards

L22 DNA Repair and Associated Disorders Flashcards

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1
Q

what are the short term consequences of DNA damage?

A
  • reduced proliferation
  • altered gene expression
  • cell death = apoptosis
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2
Q

what are the 2 major types of DNA mutations?

A
  • induced

- spontaneous

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3
Q

what are the 2 classes of spontaneous mutation?

A
  • errors of replication

- spontaneous lesions

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4
Q

what stage of cell division does Error of replication occur?

A

S phase

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5
Q

in Errors of replication, wrong base is incorporated by what? due to what?

A

DNA polymerase due to the chemistry of the nucleotides

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6
Q

define tautomerism

A

ability of certain chemicals to exist as a mix of 2 interconvertible isomers

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7
Q

what are the 2 functions of DNA polymerase?

A
  • 5’ to 3’ polymerase activity
  • 3’ to 5’ exonuclease activity

both for proofreading!

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8
Q

what is the defect in Bloom syndrome?

A

defect in BLM gene = RecQL3 DNA HELICASE!

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9
Q

what is the DNA helicase in Bloom syndrome normally required for when its not defective?

A

replication repair and recombination

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10
Q

what are sx/sx of Bloom syndrome?

A
  • smaller
  • narrow chin
  • FACIAL RASH
  • diabetes, neuro, lung, immune system deficiencies
  • high incidence of cancer
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11
Q

what genetic manifestation is seen in Bloom syndrome?

A

chromosomal instability which results in increase sister chromatid exhanges

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12
Q

what is the defect in Fanconi Anemia?

A

multiple genes (N8)
Fanc A->H
related to DNA repair
Fanc A = 65 % of cases

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13
Q

what genetic manifestation is seen in Fanconi anemia?

A

increase spontaneous chromosome breakage which is increased by DNA cross linking agents

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14
Q

what are sx/sx of falcon anemia?

A 
radial ray defects
pancytopenia
Mental retardation
short
increased risk of neoplasia
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15
Q

where do frameshift mutations tend to occur?

A

at positions where there are base repeats

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16
Q

what are frameshift mutations thought to result from?

A

‘slipping’ of DNA polymerases during replication of these repeats

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17
Q

what types of cells do spontaneous lesion occur in? due to what?

A

resting cells

due to the chemical nature of the DNA

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18
Q

what are the 3 main types of spontaneous lesions?

A
  • depurination (most common)
  • deamination
  • oxidative damage
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19
Q

what happens in deprivation?

  • what bond breaks?
  • what remains and what is lost?
  • what happens if it persists through replication?
A

glycosidic bond - between base and sugar in purine nt

remains - sugar-phosphate backbone
lost - base

persist - mutation can occur

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20
Q

what happens in deamination?

  • loss of what?
  • ___ deaminates to form ___
  • is it easy to fix?
A

loss of amine group from base (particularly cytosine)

cytosine deaminates to form uracil (pairs with T)

easy to fix

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21
Q

in deamination, 5-methyl cytosine deaminates to form?

  • what does it end up pairing with?
  • what is this considered?
A

thymidine

T-G pair
both normal bases, could be repaired to TA or CG

mutational hotspot!

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22
Q

methylated cytosines produce a ______

A

mutational hotspot

*note - not all positions are mutable, hotspots include things like 5-methyl cytosine or repeated bases (AAAAAA)

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23
Q

what is the key to understand mutational hotspots?

A

you can see the same mutations occurring at a high frequency

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24
Q

what is oxidative damage a result of?

A

production of RO compounds due to oxidative metabolism (superoxides, peroxides etc.)

25
Q

what does oxidative damage do to the cell?

What does this result in?

A
  • causes oxidative damage to many parts of the cell including addition of oxygen groups to nt bases
  • 8-oxo-7-hydroxyguanosine

results in misfiring with an A and potential TRANSVERSION

26
Q

what is the harm in ionizing radiation?

A

high energy particles/rays can cause many types of cell damage up and including death

also causes extensive damage to DNA (base damaging type) including HERITABLE MUTATIONS

27
Q

what does UV light generate?

A

deleterious photoproducts like cyclobutane pyrimidine dimers (CPD)
or
6-4 photoproducts (6-4 PP)

28
Q

what type of linkages form as a result of UV light?

what does that interfere with?

A

covalent linkages between bases on the same strand!

interfere with normal pairing and block replication!

29
Q

what are the main indirect repair groups?

A
  • nucleotide excision
  • base excision
  • mismatch repair
30
Q

what does nucleotide excision remove? Example?

A

more than a few (up to 30) base around a damaged site like seen with UV damage

31
Q

what does base excision remove? Example?

A

a single (or a few) damaged bases like seen with methylation and oxidation

32
Q

what is mismatch repair (post replication repair) remove? Example?

A

mismatched bases from tautomerism

33
Q

what is the common mechanism for all excision repair

A

-recognize damage
-remove damaged base or region around it
-replace the excised region (using DNA polymerase)
+ligase seal

34
Q

what steps of excision repair do you need specific repair proteins for?

A

to recognize damage

and to remove damaged base or region around it

35
Q

what steps of excision repair do you need shared repair proteins for?

A

replacement of excised region

36
Q

what is the defect in Xeroderma pigmentosum?

A

mutations in 9 different NER genes are capable of producing XP

37
Q

9 possible mutations in the NER gene seen in XP is an example of..?

A

locus heterogeneity

38
Q

what are the sx/sx of XP?

A

sun sensitivity
ocular involvement
increase risk of melanomas
maybe neurologic degeneration

39
Q

DNA damage seen in XP is both ____ and ___-

A

cumulative and irreversible

40
Q

what does nucleotide excision use to remove damage nt?

A

endonuclease

41
Q

what does base excision repair use to remove damaged nt?

A

DNA glycosylases

42
Q

what does the base excision repair use to remove sugar phosphate?

A

endonuclease

43
Q

what repair mechanism is especially important with triplet expansion disorders?

A

mismatch repair

44
Q

what does mismatch repair use to recognize mismatch?

A

MMR proteins (MSH 2/6, MLH1-3, PMS2

45
Q

how does mismatch repair the excised new strand?

A

repaired by re-synthesis

46
Q

how does the cell know what is the “right” strand?

A

-prokaryotes = methylation

humans = interactions with replication machinery + methylation

47
Q

what is the defect in hereditary nonpolyposis colon cancer (HNCC)

A

mutations in mismatch repair genes MSH2*, MLH18, PMS1, 2 or MSH6

48
Q

what is the result of the mutations in HNCC?

A

MICROSATELLITE INSTABILITY

49
Q

what is micro satellite instability?

A

simple repetitive DNA sequences show size variability to inaccurate replication

50
Q

what are difficult mutations to repair?

A

double stranded breaks

*dangerous in dividing cells = may lose genetic material

51
Q

what are 2 mechanisms to deal with double stranded breaks?

A
  1. non-homologous end joining

2. recombinational repair

52
Q

what is non-homologous end joining

A

more common
does not use homologous chromosome to repair the break

more prone to error

53
Q

what is recombinational repair

A

DOES use homologous chromosome to repair the break

less error prone than NHEJ

54
Q

what is BRCA 1 and 2 involved in?

A

DNA repair or apoptosis when DNA can’t be repaired

55
Q

there are 100s of mutations that have been ID in the BRCA1 gene. What is this an example of?

A

allelic heterogeneity

56
Q

what are the serious consequences associated with mutations in DNA repair genes

A
  1. increased error rate

2. genomic instability

57
Q

what is the defect in ataxia telangiectasia?

A

defect is in ATM

58
Q

what is the structure and function of ATM?

A

serene threonine kinase

detects DNA damage (sensor) and activated cell cycle arrest and DNA repair proteins

Genetics (15 decks)

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