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Abnormal Amnio > Biochem - DNA Repair > Flashcards

Biochem - DNA Repair Flashcards

1
Q

DNA proofreading is

A

3’–>5’ exonuclease activity

Not perfect

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2
Q

Agent –> Damage

Spontaneous rxn, reactive oxygen, alkylating agents

A

Modified bases, abasic sites, ssDNA breaks

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3
Q

Agent –> Damage

UV light, polycyclic aromatic hydrocarbons

A

Pyrimidine dimers, bulky adducts

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4
Q

Agent –> Damage

Xray, antitumor Cisplatin

A

DNA insterstrand cross links, dsDNA breaks

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5
Q

Deamination
Hypoxanthine
Xanthine

A

C –> A
A –> H
G–> X

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6
Q

UV light

A

thymine pyrimidine dimers between neighboring pyrimidines

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7
Q

Reactive oxygen species ROS

A

oxidize DNA

G –> 8-oxoguanine

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8
Q

Alkylating agents

A

Methylate DNA

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9
Q

of DNA lesions per cell per day

A

100,000

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10
Q

Mutations

A

Hereditary changes in DNA
Permanent changes that can be passed down to offspring
Germline –> passed to offspring
Somatic –> lead to cancer

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11
Q

Major categories of mutations

A
  1. Point mutations in single bp changes
  2. Affecting copy number of small repeats (duplications, di tri NT repeat expansion
  3. Large insertions/deletions
  4. Chromosomal rearrangements - translocations
  5. Chromosomal abberations - loss or gain of chromosomes or large parts
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12
Q

Two DNA protection strategies

A

Damage avoidance

DNA repair

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13
Q

Damage avoidance

A

First line of defense
1 - inactivate ROS w/reducing agents or SOD
2 - Shield organisms from radiation (melanin in skin)

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14
Q

Superoxide dismutase

A

Reduces O2 –> H2O2
Catalase H2O2 –> H20
Most important in mitochondria - where ROS are made

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15
Q

DNA repair

A 
MMR
BER
NER
HR
NHEJ
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16
Q

Three R’s of DNA repair

A

1 - Damage is recognized
2 - Damage is removed
3 - Single stranded gap is replaced by DNA pol
4 - Newly synthesized DNA is ligated

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17
Q

DNA synthesis can occur outside of ___ phase

A

S phase

Can happen in different parts

18
Q

DNA Mismatch Repair MMR

A

Repairs errors that were missed by proofreading
Acts within very short time window after DNA replication
1 error / 1 billion BP

19
Q

E. Coli MMR

A

1 - parent strand is recognized
2- Mut proteins are called upon
3 - MutS recognizes and binds damaged DNA
4 -MutL joins to promote a loop structure
5 - MutH recognizes the methylated GATC and has endonuclease activity to make a nick
6 - MutH removes dNMPs in region around it
7 - Resynthesis is carried out by DNA pol III and ligase

20
Q

How is parent strand recognized in E. coli?

A

Parent is methylated at GATC sequence by DNA adenine methylation methylase
Methylation is absent in the newly synthesized DNA just after replication

21
Q

MMR comparison in eukaryotes

A

Several MutS/MutL homologs

No MutH, Dam - strand discrimination is unknown

22
Q

MMR Deficiency in eukaryotes

A

responsible for microsatellite di nucleotide instability
leads to hereditary non-polyposis colorectal cancer (HNPCC)
Autosomal dominant - polyps progress to cancer quickly

23
Q

Base excision repair (BER)

A

Repair of modified bases and uracil misincorporations

Acts at any cell cycle

24
Q

BER process

A

Modified base is cleaved by a specialized DNA glycosylase
Apurinic/apyramidic site formed by AP endo/exonuclease (lyase)
One NT gap is filled by DNA pol beta
Ligase seals gap

25
Q

Nucleotide excision repair NER

A

Acts at any cell stage
Repairs any large bulky lesions in DNA
Pyrimidine dimers, bases modified by covalent binding of polycyclic aromatic hydrocarbons PAH

26
Q

NER Process

A

1 - DNA damage is recognized
2 - Helicase unwinds the dsDNA
3 - Excinuclease binds and cleaves damaged DNA at both sides of lesion
4 - Removal of ssDNA fragment 30nt
5 - Gap filled by DNA pol (replicative or DNA pol kappa) and ligase

27
Q

Diff between human and prok excinucleases

A

Human - 30nt

Prok - 12nt

28
Q

Xeroderm pigmentosum

A

Key role in NER
Caused by defects in any of seven proteins involved in NER for humans
Skin cancer at rate of 2000x normal - extreme photosensitivity

29
Q

Transcription coupled NER TC-NER

A

specifically repairs DNA damage in actively transcribed genes
ERCC6/8
Mutation –> Cockayne syndrome

30
Q

NER

A

Damaged bases removed as oligonucleotides
Removal of UV induced damage, 20% of oxidative damage
Incision on both sides of lesion - excinuclease
Deficient in human disorders

31
Q

BER

A

Damaged bases removed as free bases
Removal of oxidative and alkylation damage
Incision on one side of lesion
Role in aging and cancer

32
Q

Homologous Recombination HR

A

Error free
Uses homologous dsDNA as a template
Can only function when sister chromatid (mitosis) or homologous chromosome (meiosis) are available
Only function in late S phase and G2 of cell cycle

33
Q

Major threat to cell survival?

A

dsDNA breaks
Single unrepaired DSB is lethal for cell
X-rays, cross linking chemical agents, endogenous free racidals hit DNA in both strands

34
Q

HR process

A

1 - dsDNA break
2 - 5–>3’ resection by exonuclease
3 - RAD51 homolgous pairing protein loads onto ssDNA to search for homolgous template
4 - Template is used for DNA synthesis
5 - 3’ end acts as primer
6 - resynthesis of other strand using newly made strand as template
7 - ligation

35
Q

Non-Homologous End Joining NHEJ

A

repairs DSB in template independent manner
Error prone
Non-random facilitated ligation of broken DNA ends
DNA loss is irreversible
Can be used at any stage of cell cycle

36
Q

NHEJ process

A

1 - dsDNA break
2 - End joining by KU70/80 and DNA-PKcs
3 - End trimming by exonucleases make the ends match up better
4 - ligation

37
Q

Deficiencies in HR

A

ATM - checkpoint kinase

38
Q

Damage Tolerance

A

Last resort
Use bypass polymerases with reduced accuracy
DNA pol dissociate from fork and bypass DNA pols attach
Error prone - responsible for damage induced mutations
POL IV, POL V in proks

39
Q

Bypass DNA polymerase

A

Lack 3–>5’ proofreading

Distributive rather than processive polymerization

40
Q

Error free/prone

A

Error Free:
MMR, BER, NER, HR
Error Prone : NHEJ, Lesion bypass

Abnormal Amnio (5 decks)

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