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CONJ 662 - Genetic Mechanisms > Test1: Lect4 Amanda McCullough > Flashcards

Test1: Lect4 Amanda McCullough Flashcards

1
Q

Nucleotide excision repair (NER):

- Repairs what?

A 
- Repairs what?
bulky adduct (Pyrimidine dimers, intra and interstrand crosslinking)
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2
Q

Describe the pathway of nucleotide excision repair pathway in bacteria:

A

UvrA and UvrB form heterotrimer (2 As, 1 B) ->
UvrC replaces UvrA and makes two incisions, 3’ and 5’ ->
Helicase mediated excision erroneous segment ->
Hifi replication enzymes replace nucleotides ->
Ligase closes the nick

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3
Q

Excision vs incision:

A

Incision: a cut/nick in the nucleotide strand (takes energy to break the bond)
Excision: Removal of DNA segment (takes energy to pry basepairs apart, often helicase mediated)

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4
Q

What was one of the first clues that repair and replication may be coupled?

A

Many repair proteins are also part of the transcription complex

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5
Q

Nucleotide excision repair (NER):

- Steps in human:

A

Recognition and verification (you have to make sure your right before you cut up the genome)
5’ Incision (point of no return)
Repair replication (Minimizes exposure of ssDNA to mutagenic cellular environment, by not completing 2nd incision before replication)
3’ Incision
Excision
Rejoining

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6
Q

How do you verify the damage, (how would a glycosylase do this for example):

A

base pair flipping. The track along helix til you find something wrong, flipping out the nucleotides into a pocket in the protein which checks the nucleotide.
- Mismatch will check both bases

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7
Q

What does this mean “Nucleotide excision repair is the most “general” of repair pathways”

A

1: NER doesn’t look for specific mutations, they just look for general errors.
2: This means NER is what helps with new carcinogens. We haven’t evolved any SPECIFIC way to deal with formaldehyde, but NER can just cut out the messed up section

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8
Q

Name a disease caused by a failure in nucleotide excision repair pathway, specifically in Global Genomic Repair::

A

Xeroderma pigmentosum

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9
Q 
Xeroderma pigmentosum (XP):
- Symptoms and explanation:
A
  • Symptoms:
    Failure of Global Genomic Repair = CANCER
    Severe sun sensitivity (cannot repair UV damage)
    Skin cancer (from UV damage and other exposures)
    30% neurological problems (failure to repair problems in CNS)
    Tend to have early death from cancer
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10
Q

How is Xeroderma pigmentosum treated?

A

It isn’t really treated. You minimize sun exposure, includes using UV filters, and night activities.

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11
Q

Is Xeroderma Pigmentosum dominant or recessive?

Germline or somatic?

A 
Autosomal recessive
Germline mutation (inherited it)
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12
Q

What can cells with Xeroderma Pigmentosum not do?

A

Cannot do repair replication, in NER (process of adding nucleotides while the damaged strand is slowly pealed away)
Cannot do the 5’ initial incision in NER

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13
Q

Different phenotypes of XP made people think that there was different mutations causing it.
How was this tested?

A

Complementation. Patients cells with a known mutation were tested against patient cells with an unknown mutation. Cells were fused, and given h thymadine a radiolabel. UV exposure, if cells underwent repair radiolabelled T would be added and could be seen later.
If combined cells are equally sensitive as before, they have the same genetic defect.

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14
Q

How many genes are involved in XP?

- How is XP assayed/diagnosed?

A

at least 8, may be more. And multiple variations may cause it XP.
- How is XP assayed/diagnosed?
1: UV sensitivity assay of patient cells in Vivo
2: Complementation testing
Sequence gene (though made difficult because of reasons listed above)

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15
Q

What are the two types of NER?

A

Global Genomic Repair: the one we’ve been talking about

Transcription coupled repair

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16
Q

How does transcription coupled repair (NER) differ from global genomic repair (NER)?

A

1: Instead of having UvrA and UvrB analog find the adduct, the polymerase stalls at it it.
2: Polymerase recruits CSA and CSB which starts the same pathway as global genomic repair (GGR) from here on out.

17
Q

What pathways are used during transcription transcription coupled repair (TCR)?

A

BER, NER and translesion synthesis polymerases

18
Q

Theories as to why transcription coupled repair is important:

A
  • Restart Transcription (allows repair and then start over of transcription)
  • Is this just a DNA damage surveillance system?
  • Is this a system which measures damage to decide when cell death is necessary?
19
Q

What happens if you have a defect in CSA or CSB (a key protein in TCR)?
- What, noticeably, is not happening?

A

Cockayne syndrome
- What, noticeably, is not happening?
No skin cancer

20
Q

Cockayne syndrome:

  • Symptoms
  • Why no cancer?
  • Genetics:
A 
- Symptoms
Cellular UV sensitivity
Defective repair of transcribed genes
Neuronal issues (unusual myelination 
Deafness, dwarfism, retinopathy
No skin cancer
2 complementation
- Why no cancer?
TCR is what they are deficient in, this causes cell death when lost but not cancer
- Genetics:
1: 2 complementation groups (CSA and CSB)
2: autosomal recessive
21
Q

cockayne syndrome + XP?

  • Symptoms:
  • Complementation groups (what is targeted)?
A

Yes
- Symptoms:
Defective global and transcription coupled repair
- Complementation groups (what is targeted)?
2, XPB, XPD (both helicases, necessary for both global and transcription)

22
Q

XP Variants still make incision breaks correctly, but have XP, why?

A

Error in Pol eta, a translesion polymerase which is in charge of error free DNA repair

23
Q

Where do mutations tend to occur which cause mutator phenotype in pol eta?

A

in the palm, where it interacts with the DNA

24
Q

Translesion Polymerases:

  • Also called?
  • Differ in what way structurally?
  • Traits:
A 
- Also called?
Slopier copiers
- Differ in what way structurally?
Looser "finger and thumb", allows replication past adducts
- Traits:
1: Poor replication accuracy
2: Favored formation of non watson-crick base pairs
3: can replicate past DNA damage
4: Poor processivity
25
Q
  • How are translesion polymerases recruited?
  • Do they fix the damage?
  • There are varieties, why?
A
  • How are translesion polymerases recruited?
    pol delta stalls, PCNA helps to change affinity, translesion polymerase recruited, replicate past damage, pol delta takes back control.
  • Do they fix the damage?
    No, just bypass it.
  • There are varieties, why?
    They specialize in bypassing specific types of damage. Pol eta bypasses pyramidine dimers (T-T)
26
Q

How can inhibition of TLS (translesion synthesis) polymerases help patients with cancer?

A

In some cases, overexpression of these protects cancer cells from chemotherapeutics.

27
Q

DNA damage response (the bacterial version):

  • Define:
  • Also called:
  • Turned on by:
A 
- Define:
turns on 43 genes whenever DNA is damaged
- Also called:
SOS response
- Turned on by:
Anything which damages DNA (UV light)
28
Q

How does the SOS response occur

A 
DNA damaged ->
ssDNA ->
Binds RecA ->
RecA bound to ssDNA cuts LexA ->
LexA is the repressor of ~43 genes ->
Now they are on instead of off
29
Q

RecA:

A

Binds ssDNA to cut lexA (a repressor), involved in SOS.

30
Q

lexA:

A

A repressor of many genes, cut by RecA in the SOS response

31
Q

Mammalian DNA damage response (DDR):

A

A lot of shiz goes down.

  • Chromatin modification
  • Translation regulation
  • Transcription regulation
  • Protein synthesis regulation
  • Protein degradation regulation
  • Protein modification
  • Macromolecular complex formation
32
Q

Mammalian DNA damage response (DDR):

- Two kinetics:

A
  • Two kinetics:
    Fast: protein posttranslational modification
    Slow: gene expression and protein synthesis changes
33
Q

Mammalian DNA damage response (DDR):

- Steps:

A

Recognize double stranded break break forms, some type of damage ->
Kinases have phosphorylation cascade (H2AX phosphorylation) ->
Cells arrest (give time to fix it) ->
Cannot fix it then cell death

34
Q

H2AX phosphorylation:

A

Response to double strand break
Considered a marker of DNA damage.
It is a phosphorylation of the H2AX (Histone 2 AX H2AX, axe made DS break) on chromosomes.
- Spread 2 Mb from site of double strand break

CONJ 662 - Genetic Mechanisms (13 decks)

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