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Genetics > L22 DNA Repair and Associated Disorders > Flashcards

L22 DNA Repair and Associated Disorders Flashcards

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
what does oxidative damage do to the cell? | What does this result in?
- 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
what is the harm in ionizing radiation?
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
what does UV light generate?
deleterious photoproducts like cyclobutane pyrimidine dimers (CPD) or 6-4 photoproducts (6-4 PP)
28
what type of linkages form as a result of UV light? | what does that interfere with?
covalent linkages between bases on the same strand! interfere with normal pairing and block replication!
29
what are the main indirect repair groups?
- nucleotide excision - base excision - mismatch repair
30
what does nucleotide excision remove? Example?
more than a few (up to 30) base around a damaged site like seen with UV damage
31
what does base excision remove? Example?
a single (or a few) damaged bases like seen with methylation and oxidation
32
what is mismatch repair (post replication repair) remove? Example?
mismatched bases from tautomerism
33
what is the common mechanism for all excision repair
-recognize damage -remove damaged base or region around it -replace the excised region (using DNA polymerase) +ligase seal
34
what steps of excision repair do you need specific repair proteins for?
to recognize damage | and to remove damaged base or region around it
35
what steps of excision repair do you need shared repair proteins for?
replacement of excised region
36
what is the defect in Xeroderma pigmentosum?
mutations in 9 different NER genes are capable of producing XP
37
9 possible mutations in the NER gene seen in XP is an example of..?
locus heterogeneity
38
what are the sx/sx of XP?
sun sensitivity ocular involvement increase risk of melanomas maybe neurologic degeneration
39
DNA damage seen in XP is both ____ and ___-
cumulative and irreversible
40
what does nucleotide excision use to remove damage nt?
endonuclease
41
what does base excision repair use to remove damaged nt?
DNA glycosylases
42
what does the base excision repair use to remove sugar phosphate?
endonuclease
43
what repair mechanism is especially important with triplet expansion disorders?
mismatch repair
44
what does mismatch repair use to recognize mismatch?
MMR proteins (MSH 2/6, MLH1-3, PMS2
45
how does mismatch repair the excised new strand?
repaired by re-synthesis
46
how does the cell know what is the "right" strand?
-prokaryotes = methylation humans = interactions with replication machinery + methylation
47
what is the defect in hereditary nonpolyposis colon cancer (HNCC)
mutations in mismatch repair genes MSH2*, MLH18, PMS1, 2 or MSH6
48
what is the result of the mutations in HNCC?
MICROSATELLITE INSTABILITY
49
what is micro satellite instability?
simple repetitive DNA sequences show size variability to inaccurate replication
50
what are difficult mutations to repair?
double stranded breaks *dangerous in dividing cells = may lose genetic material
51
what are 2 mechanisms to deal with double stranded breaks?
1. non-homologous end joining | 2. recombinational repair
52
what is non-homologous end joining
more common does not use homologous chromosome to repair the break more prone to error
53
what is recombinational repair
DOES use homologous chromosome to repair the break less error prone than NHEJ
54
what is BRCA 1 and 2 involved in?
DNA repair or apoptosis when DNA can't be repaired
55
there are 100s of mutations that have been ID in the BRCA1 gene. What is this an example of?
allelic heterogeneity
56
what are the serious consequences associated with mutations in DNA repair genes
1. increased error rate | 2. genomic instability
57
what is the defect in ataxia telangiectasia?
defect is in ATM
58
what is the structure and function of ATM?
serene threonine kinase detects DNA damage (sensor) and activated cell cycle arrest and DNA repair proteins

Genetics (15 decks)

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