Molecular Mechanisms of Mutation Flashcards

1
Q

When mutations occur due to internal cellular factors, what is this called

A

spontaneous mutation

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2
Q

When mutations occur due to outer external factors, what is this called

A

induced mutations

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3
Q

Most DNA damage is caused by internal factors generated by normal metabolic processes inside the cell by…

A

water (hydrolysis)
oxygen (oxidation)
alkylating agents (alkylation)

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4
Q

What is the frequency of error in nucleotides within replication

A

less than 1 in a billion - it is very accurate

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5
Q

What is meant by mispairing due to other structures

A

arise through the wobble effect via flexibility in the helical structure of DNA causing base pairs to match incorrectly
OR
by protonated forms of bases

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6
Q

What could cause incorperated and replicated errors

A

tautomeric shifts or the wobble effect

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7
Q

What are two causes of deletions and insertions

A

strand slippage and unequal crossing over in meiosis

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8
Q

What is strand slippage

A

when a newly synthesized strand loops out resulting in the addition of one nucleotide on the new strand
OR
when the template strand loops out, resulting in the omission of one nucleotide on the new strand

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9
Q

What is unequal crossing over

A

exactly how it sounds
- homologous chromosomes misalign during crossing over where one crossover contains an insertion and one crossover contains a deletion

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10
Q

What is depurination

A

breakage of the covalent bond between the purine base and the 1’ carbon atom of the deoxyribose sugar

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11
Q

What does depurination create

A

an apurinic site

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12
Q

What is the resulting defect of depurination

A

no complement base can be added so a random nucleotide is incorporated (usually an A)

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13
Q

What is deamination

A

the loss of an amino group, typically from cytosine
- gives rise to uracil, which will pair with adenine during replication
- then, in the next cycle A will pair with T
*end result is a C-T transition

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14
Q

What is the long term result of deamination

A

over time, genomes become more AT rich and CG poor

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15
Q

What is a mutagen

A

an environmental agent that increases mutation rate above the spontaneous rate

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16
Q

What are the common classes of mutagen

A

base analogs
alkylating agents
deaminating chemicals
hydroxylamine
oxidative radicals
intercalating agents
radiation

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17
Q

What are base analogs

A

chemicals with structure similar to the 4 nucleotides

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18
Q

What is an example of a base analog

A

5-bromouracil (5BU) - an analog of thymine
2-aminopurine (2AP) - an analog of adenine

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19
Q

What are alkylating agents

A

mutagens that react with DNA bases and add methyl or ethyl groups

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20
Q

What is an example of an alkylating agent

A

ethylmethylsulfonate (EMS) and mustard gas

21
Q

What is a deaminating chemical

A

addition to spontaneous deamination noted for spontaneous chemical changes

22
Q

What is an example of a deaminating agent

A

nitrous acid

23
Q

What is the function of nitrous acid

A

changes cytosine to thymine (C-T transition)
changes adenine to hypoxanthine which can pair to C (A-G transition)
change guanine to xanthine which can pair to T (G-A transition)

24
Q

What is hydroxylamine

A

very specific base modifying mutagen
- adds hydroxyl group to cytosine (hydroxylaminocytosine) which increases the rare tautomer that pairs with adenine

only effects cytosine
(C-T transition)

25
Q

What are oxidative radicals

A

reactive forms of oxygen that are produced through normal aerobic metabolism (or by chemicals/radiation)

26
Q

What are intercalating agents

A

sandwich themselves between adjacent base pairs to distort the DNA helix

27
Q

What is the end result of intercalating agent mutation

A

insertions or deletions - frameshifts

28
Q

What are examples of an intercalating agents

A

ethidium bromide, acridine orange, dioxin, proflavin

29
Q

What is the defect of x-ray radiation

A

breaks phosphodiester bonds leading to double stranded breaks

30
Q

What is the defect of UV radiation

A

induces chemical bonds between two adjacent pyrimidine molecules on the same strand
(thymine dimers are the most frequent)

31
Q

What are the 2 general features of DNA repair

A

mechanisms require double stranded DNA
DNA repair has built in redundancy

32
Q

What is mismatch repair (MMR)

A

MMR identifies the new strand, and degrades the new strand between the nick and mismatched bases
- poly and ligase fill the gap using the old strand as the template

33
Q

How does MMR recognize the new vs old strand in prokaryotes

A

the new strand is methylated, the old is not

34
Q

How does MMR recognize the new vs old strand in eukaryotes

A

we don’t know (there is no methylation)

35
Q

What happens when a mutation in MMR function arises

A

elevated somatic mutations - cancer

36
Q

What is direct repair

A

reversal of mutation - restores original structure

37
Q

What is base excision repair

A

DNA glycosylases excise the damaged base(s)
- enzymes are specific for each modified base

only the base is removed first - leaves an apurinic or apyrimidinic site

Other enzymes then remove the sugar afterward

DNA poly fills the gap and DNA ligase seals the nick

38
Q

What breaks the phosphodiester bond between base and sugar in base excision repair

A

AP endonuclease (AP stands for apurinic/apyrimidinic)

39
Q

Is base excision one step or multistep

A

multi step - base is removed first then sugar

40
Q

What is nucleotide excision repair

A
  • An enzyme complex recognizes the distortion in the DNA sequence and binds
  • then DNA is seperated and single stranded binding proteins stabilize the single strands
  • phosphodiester bonds on either side of the mutation are broken
  • damaged strand removed by helicase
  • gap is filled by polymerase and sealed by ligase
41
Q

What is different between base excision repair and nucleotide excision repair

A

base excision repair - multistep (base removed first then sugar after)
nucleotide excision repair: base and sugar removed simultaneously as a unit (long strand is removed all at once)

42
Q

What causes double stranded breaks

A

ionizing radiation
oxidative radicals
other damaging DNA agents

43
Q

What is a double stranded break

A

both strands of the DNA helix are broken

44
Q

Does a double stranded break cause mutation on its own

A

no, but it stalls DNA replication and could lead to chromosomal rearrangements (causing deletions, duplications, insertions, etc)

45
Q

What are the two pathways to repair double stranded breaks

A

homology directed repair (HDR)
non homologous end joining (NHEJ)

46
Q

What is homology directed repair (HDR)
- also known as homologous recombination

A

repairs a broken DNA strand with the genetic information contained in the sister chromatid (same system as crossing over it meiosis)

47
Q

What is non homologous end joining (NHEJ)

A

independent of the homologous template - often occurs during the G1 phase (no sister chromatid is present here)

  • proteins recognize broken ends of DNA an bind them together, leading to deletions insertions and translocations
    *this is important in somatic recombination (no meiosis here)
48
Q

What types of repair can fix DNA dimers

A

direct repair
base excision
nucleotide excision