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CONJ 662 - Genetic Mechanisms > Test1: Lect3 Amanda McCullough > Flashcards

Test1: Lect3 Amanda McCullough Flashcards

1
Q

Define Mutagenesis:

A

A process by which genetic information is changed in a stable and heritable manner

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2
Q

Mutation:

  • Germline define:
  • Somatic define:
A
  • Germline define:
    1: In gametes, will be passed on
    2: for a child a germline mutation is inherited
  • Somatic define:
    1: In gametes, will not be passed on
    2: for a child a germline mutation is acquired
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3
Q

Mutation:
Vs.
Polymorphism:

A

Mutation: Difference in DNA sequence of individual which is rare in a population and may be unique to the individual
Polymorphism: Difference in DNA sequence found in many individuals, at a specified frequency (usually > 1%)

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4
Q

SNPs:

A

single nucleotide polymorphism, occurs approx. 1/360 nucleotides.

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5
Q

monogenic disease:

  • Define:
  • Examples of:
A
  • Define:
    A disease caused by a one gene mutation
  • Examples of:
    Hemophilia and sickle cell anemia
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6
Q

multifactorial disease:

  • Define:
  • Examples of:
A
  • Define:
    Multiple gene and environment interactions
  • Examples of:
    Heart disease, diabetes
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7
Q

Gene-environment interactions:

  • Define:
  • Examples of:
A
  • Define:
    Susceptibility to endogenous agents and environment:
  • Examples of:
    Smoking -> lung cancer
    Sun exposure -> skin cancer
    Note: there are genes which make people MORE susceptible to these.
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8
Q

Vicious cycle of aging:

A 
Aging ->
Accumulation of mutations ->
Deregulation of transcription, impaired stress response ->
Decline in DNA repair ->
More mutations ->
Aging ->
etc.
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9
Q

Mutator phenotype:

- Define:

A
  • Define:
    1: A mutation in a gene involved in DNA repair or in ensuring DNA fidelity during replication, or in apoptosis (ability to kill yourself if dangerously mutated)
    2: AKA a gene which when mutated will allow more mutants later
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10
Q

Senescence:

  • Define:
  • What can cause senescence:
A
  • Define:
    When cells appear to lose the ability to divide and grow. They just kind of sit there.
  • What can cause senescence:
    1: Mutations.
    2: Similar to the vicious cycle of aging.
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11
Q

Elephants are much larger than us, have many more cells than us, but get cancer less often or as often as us, why the paradox?

A

1: Elephants have 50 TP53 alleles, which results in about twice the cell apoptosis as us.
2: Simply, they kill their cells if they have cancer potential a lot sooner than we do, and don’t try to repair them.

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12
Q

Could you just stimulate apoptosis systemically?

A

Maybe, but in addition to killing cancer cells you may have diseases like Alzheimer develop, which also has high apoptosis.

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13
Q

Point mutation which doesn’t change the protein the codon is codes for:

A

Synonymous mutation.

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14
Q

Point mutation which changes the protein the codon is codes for, BUT the amino acid is chemically similar:

A

missense mutation (Conservative)

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15
Q

Point mutation which changes the protein the codon is codes for, AND the amino acid is chemically different:

A

missense mutation (nonconservative)

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16
Q

Uh oh! Did that mutation just cause a premature stop codon?

A

Nonsense mutation

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17
Q

Frameshift mutations come in two flavors, what are they?

A

Base insertion

Base deletion

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18
Q

Transition mutation define:

A 
Purine to purine (A to G)
Pyrimidine to pyrimidine (T to C)
A - T to G - C
or
G - C to A - T
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19
Q

Transversion mutation define:

A 
Purine to Pyrimidine (A to T)
Pyrimidine to purine (C to G)
A - T to T - A
or
G - C to C - G
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20
Q

Mechanisms of spontaneous mutations:

A
  • Unrepaired Spontaneous lesions:
    1: Depurination
    2: Deamination
    3: Oxidation
  • Replication
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21
Q

Depurination:

  • Define:
  • How does a polymerase deal with lack of base information?
A
  • Define:
    Loss of a purine or pyrimidine base (yes both same name)
  • How does a polymerase deal with lack of base information?
    Most standard replication polymerases just add an A (the A rule)
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22
Q

Deamination of bases:

  • Define:
  • Common examples:
A 
- Define:
Amine to ketone
- Common examples:
(cytosine a problem child)
Cytosine -> Uracil
5 methylcytadine -> thymine
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23
Q

Oxidative damage:

  • Define:
  • Common example:
  • Sources of oxidative agents:
A 
- Define:
Damage caused by oxidative species (like oxygen)
- Common example:
8 - hydroxyguanine (ketone at 8 position)
- Sources of oxidative agents:
Heterocyclic amines
Oxygen
Exercise
Alcohol
Tobacco
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24
Q

What do polymerases like to put across from 8 - hydroxyguanine?

A

An adenine (fits better than cytosine)

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25
Q

Environmental (induced) mutagenesis:

  • Define:
  • Examples:
A
  • Define:
    Exposure to substances or wavelengths in environment which cause mutagenesis.
  • Examples:
    Smoking Tobacco (Increases oxidative species)
    Heterocyclic amines (browning meat)
    Acrolein (gasses produced in air)
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26
Q

Radiation and chemical (induced mutagenesis):

  • Define:
  • Examples:
A
  • Define:
    This is really a form of environmental mutagenesis. But different because you could have a high isolated exposure, chemical spill, etc.
  • Examples:
    Mustard gas
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27
Q

What is it important to remember when working with DIFFERENT mutagens on a cell line?
- Ideal survival percent?

A

They are not all created equal. You have to use equally toxic amounts of the two (which will likely be different amounts, depending on their toxicities)
- Ideal survival percent?
>35% survival, so you don’t just kill them all

28
Q

Cisplatin:

  • What is it?
  • Why is it effective?
A
  • What is it?
    A chemotherapeutic drug
  • Why is it effective?
    Crosslinking agent
29
Q

Types of crosslinking DNA-damage:

- Define them as well:

A

Intrastrand crosslink: Covalent crosslinking between bases on the same strand
Interstrand crosslink:
Crosslinking of bases on two different strands (but usually the same duplex?

30
Q

Which type of crosslinking is the worst?

Why?

A

Interstrand crosslinking.

Cannot even pull the strands apart

31
Q

Name a type of intrastrand crosslinking:

A

Thymine-thymine dimerization from UV

32
Q

What induces DNA interstrand crosslinks?

A

Many chemotheuraputics, like cisplatin

33
Q

Complementation:

A

Defined previously.
production of a wild type phenotype when 2 genomes bearing a different recessive mutation are united in the same cell (cell fusion/crosses)

34
Q

Epistasis:

  • Define:
  • Conclusion:
A
  • Define:
    I knock out gene 1 (g1), and my phenotype drops from 10 to 5.
    I knock out gene 2 (g2), and my phenotype drops from 10 to 7.
    I knock out g1 and g2, and my phenotype drops from 10 to 5 (same as g2).
  • Conclusion:
    The genes are in the same pathway. It doesn’t get worse with the double knockout, because the pathway is fried when g1 is knocked out.
35
Q

Additivity:

  • Define:
  • Conclusion:
  • Also called:
A
  • Define:
    I knock out gene 1 (g1), and my phenotype drops from 10 to 5.
    I knock out gene 2 (g2), and my phenotype drops from 10 to 7.
    I knock out g1 and g2, and my phenotype drops from 10 to 2 (lower than both).
  • Conclusion:
    The genes are in different pathways. It gets worse in the double knockout, so i probably fried to seperate pathways which support the phenotype.
  • Also called:
    Non epistatic.
36
Q

Name repair pathways (asterisk by one not being taught this course):

A 
Mismatch repair
Base excision repair
Nucleotide excision repair
Damage bypass (translesion synthesis)
* Double-strand break repair
37
Q

Mismatch Repair (MMR):

  • Responsible for:
  • Linked to:
A
  • Responsible for:
    Repairing mismatched bases and small “loop outs” (IDLs)
  • Linked to:
    Replication, occurs in a post-replication repair pathway
38
Q

How does E. coli identify the new strand from the template strand for purposes of mismatch repair?

A

1: It methylates adenines.
2: There is a delay in methylation post replication.
3: The methylated strand is right.

39
Q

MMR in bacteria
MutS:
(in bacteria)

A

Searches for/recognizes mismatched pairs

(Link most of time searching)

40
Q

MMR in bacteria
MutL:
(in bacteria)

A 
Coordinator protein (helps keep MutH in check)
(You need something to link)
41
Q

MMR in bacteria
MutH:
(in bacteria)

A

Endunuclease for strand nicking, cuts opposite of the methylated strand
(Hiya to cut it, Link goes Hiya)

42
Q

How do bacteria do mismatch repair?

A

Delay in methylation!
MutS identifies mismatch ->
MutL works to position and confirm MutH ->
MutH cuts the strand ->
Helicase and polymerases come in and make a new strand.
Methylation occurs

43
Q

What if a bacteria over-expressed DAM methylase? How would this effect mismatch repair?

A

We would see less delay between new strand synthesis and methylation. Repair proteins would have a hard time identifying the template strand.

44
Q

Do humans have a mutH homolog?

A

No. They use a endonuclease which complexes with PCNA. Theorizes PCNA can help with recognition of nascent strand vs template strand.

45
Q

How is mutS different in humans?

A

to proteins in a heterodimer (they are different proteins) will form the initial recognition process

46
Q

What is the current model for how strand specificity is determined for MMR in humans?

A

The mutL homolog complexes with PCNA.
The mutH homolog interacts with PCNA for interaction.
This could impart knowledge of which strand is nascent (newly synthesized)

47
Q

On lagging strand do you need a mutH homolog to create a nick?

A

No, there are already nicks. More importantly nicks are on the nascent strand.

48
Q

How do you use mismatch repair for somatic hypermutation (useful for antibody generation):

A

AID enzyme creates G - U mutant ->
These are recognized by mutS analogs ->
PCNA and other are recruited, but PCNA is MONOUBIQUINATED ->
Monoubiquinated PCNA recruits a low fidelity polymerase (pol eta) instead of a high fidelity one (as it normally for MMR) ->
Low fidelity polymerase makes mistakes ->
More errors occur

49
Q
  • Name a disease caused by failure of mismatch repair:

- What are the symptoms:

A
  • Name a disease caused by failure of mismatch repair:
    HNPCC (hereditary nonpolyposis colon cancer), aka lynch syndrome (link could fight a lynch… if he wasn’t broken ;P )
  • What are the symptoms:
    High chance of colorectal cancer (~50%), high chance of undometrium cancer (~50%), and high chance of ovarian cancer (~10%)
50
Q

To cause lynch syndrome what mutation must occur in MMR?

A

Any mutation which causes failure of a protein in the process.

51
Q

What is microsatellite instability (MSI)?

- How is it caused?

A

Somatic increase of small repeat sequences
- How is it caused?
NUMBER 1 is more common in lynch syndrome!
1: Repeat sequences form small hairpin structures, on the nascent strand this results in elongation, the Pol will read the sequence again
2: Repeat sequences form small hairpin structures, on the template strand this results in shortening of the strand, the Pol will read the sequence again

52
Q

In what disease is microsatellite instability a characteristic sign?
- Why?

A

Lynch syndrome
- Why?
MMR repair is what would normally remove the small hairpin structures, failure to do so results in microsatellite instability

53
Q

What broader category is microsatellite instability apart of?

A

Replication slippage. Whenever the polymerase skips a sequence (slips over it) or slips back on a sequence and repeats it.

54
Q

Base Excision Repair (BER):

  • Responsible for:
  • Linked to:
  • Some examples of types of damage:
A
  • Responsible for:
    Alterations to bases, including some alterations which result in mismatches (There is overlap with some enzymes of BER and MMR)
  • Linked to:
    Nothing specific, this is a housekeeping pathway (Base, homebase, housekeeping), it is always on.
  • Some examples of types of damage:
    Oxidation, depurination, etc.
55
Q

Why is BER important in the brain?

A

It is not associated with replication, since the brain is not replicating (usually), it is one of the few pathways for repair which works in the brain

56
Q

How does BER work?

A

Error in base recognized ->
Glycosylase removes the base ->
AP site now exists, AP nuclease makes a cut ->
1 - 6 nucleotide gap is made by removal of nucleotides ->
Resynthesized ->
Ligase seals nick

57
Q

ap site define:

A

apurinic/apyrimidinic site

58
Q

Some differences between MMR and BER?

A

MMR replication linked, BER constitutionally active
MMR cuts out larger sequences, BER cuts out smaller
BER and MMR recognize different types of damage

59
Q

Why are glycosylases called glycosylase?

- Why aren’t glycosylase knockouts embryonic lethal?

A

Cut bond between sugar and base
- Why aren’t glycosylase knockouts embryonic lethal?
There is likely a redundant pathway which fixes these issues

60
Q

What two pathways can BER take?

A

Short patch:

Long patch:

61
Q

Short patch BER:

A

All the same, but only 1 to 2 nucleotides are removed and specialized polymerase which only adds 1 to 2 nucleotides replaces them (pol beta)

62
Q

Long patch:

A

1: replacement of nucleotides is accomplished by normal high fidelity replication machinery (pol delta, pol sigma, PCNA)
2: 5’ end cut, nucleotides moved out of the way as replication occurs, 3’ end cleaved, excised. Minimizes exposure of ssDNA to mutagenic cellular environment.
3: 2 - 12 nt covered

63
Q

Why is repair regulation so tightly regulated?

A

You don’t want to start a job unless you have all the proteins to finish it (don’t want to leave gaps).

64
Q

Example of BER Deficiency:

  • Cause:
  • Symptoms:
A 
MUTYH Polyposis Syndrome (type of colon cancer)
- Cause:
biallelic mutations in MUTYH (mutY)
- Symptoms:
Colon cancer (fastest replicating cells)
65
Q

What does MUTYH (mutY homolog) do?

A

1: It removes A opposite an 8 - hydroxyguanine.
2: Doesn’t remove the 8-hydroxyguanine, so doesn’t fix the actual problem, just delays it
3: It must also be able to recognize strand specificity, because it doesn’t remove 8 - hydroxyguanine triphosphates added opposite an A during replication

66
Q

IDLs:

  • Stands for?
  • Associated with?
A
  • Stands for?
    Insertion deletion loops (microsatellite)
  • Associated with?
    MMR

CONJ 662 - Genetic Mechanisms (13 decks)

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