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Medical Biochemistry > Ch. 22: DNA Replication, Repair, & Mutagenesis > Flashcards

Ch. 22: DNA Replication, Repair, & Mutagenesis Flashcards

1
Q

What are the 3 general features of DNA replication?

A

1) DNA replication is semiconservative
2) Replication is bi-directional
3) Replication is semi-discontinuous

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2
Q

What were the 3 proposed models of DNA replication? Describe each.

A

1) Conservative Replication: parent molecule directs synthesis of new double-stranded molecule; after 1 round of rep ➡️ one molecule conserved as 2 old strands
2) Semi-conservative Replication: 2 parent strands separate, each makes copy of itself; after 1 round of rep ➡️ 2 daughter molecules both have 1 new & 1 old strand
3) Dispersive Replication: Random distribution of parent material between 2 daughter molecules

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4
Q

What are the 3 active sites on E. coli DNA polymerase I? What is the function of each site?

Which one is the smaller fragment? Which two are part of the larger fragment?

A

1) 3’ to 5’ exonuclease activity: proofreading & editing
2) 5’ to 3’ exonuclease activity: DNA repair
3) 5’ to 3’ polymerase activity: nick translation (nick & replace old strand)

Smaller fragment: 5' exonuclease
Larger fragment (Klenow fragment): polymerase & 3' exonuclease
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5
Q

What is the chief DNA replicating enzyme of E. coli?

Which subunits have polymerase function? Which subunits have proofreading ability (3’ to 5’ exonuclease)?

A

E. coli DNA polymerase III

Alpha subunits: polymerase function
Epsilon subunits: proofreading ability

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6
Q

E. coli DNA polymerase I & III: Molecular weight of each?

A

Polymerase I: 105,000

Polymerase III: 130,000

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7
Q

E. coli DNA polymerase I & III: How many molecules/cell for each?

A

Polymerase I: ~400

Polymerase III: ~10

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8
Q

E. coli DNA polymerase I & III: How many nucleotides/second for each?

A

Polymerase I: ~20

Polymerase III: ~1000

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9
Q

E. coli DNA polymerase I & III: which has 3’ Exonuclease activity?

A

Polymerase I: yes

Polymerase III: no

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10
Q

E. coli DNA polymerase I & III: which has 5’ Exonuclease activity?

A

Polymerase I: yes

Polymerase III: no

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11
Q

E. coli DNA polymerase I & III: what is the biological function of each?

A

Polymerase I: RNA primer excision, DNA repair

Polymerase III: Replicase

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12
Q

What experiment showed DNA replication is semiconservative?

A

Meselson and Stahl experiment

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13
Q

Where in the cell is eukaryotic DNA polymerase alpha located?

What is its biological activity?

A

Nucleus

Replication (primase, replication initiator)

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14
Q

Where in the cell is eukaryotic DNA polymerase beta located?

What is its biological activity?

A

Nucleus

DNA repair (base excision repair)

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15
Q

Where in the cell is eukaryotic DNA polymerase gamma located?

What is its biological activity?

A

Mitochondria

Mitochondrial DNA replication

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16
Q

Where in the cell is eukaryotic DNA polymerase delta located?

What is its biological activity?

A

Nucleus

Replication (main polymerase at leading & lagging strand)

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17
Q

Where in the cell is eukaryotic DNA polymerase epsilon located?

What is its biological activity?

A

Nucleus

Replication (leading & lagging strand)

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18
Q

What are the main eukaryotic DNA polymerases?

A

DNA polymerases alpha and delta

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19
Q

What are the 3 enzymatic activities of reverse transcriptase?

A

1) RNA-directed DNA polymerase activity
2) RNase H activity: exonuclease that specifically degrades RNA chains in DNA:RNA hybrids
3) DNA-directed DNA polymerase activity: replicates ssDNA, forms dsDNA

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20
Q

What is an example of a reverse transcriptase?

What drug inhibits this enzyme?

A

HIV reverse transcriptase

AZT (3’-azido-2’,3’-dideoxythymidine): ➖ DNA synthesis

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21
Q

What enzymes are used to unwind the DNA helix?

A

DNA gyrase: ATP dependent negative supercoiling

Helicase: ATP dependent unwinding of DNA double helix

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22
Q

What enzyme, as an RNA polymerase, synthesizes DNA primers?

A

Primase

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23
Q

What enzyme seals nicks in dsDNA?

A

DNA ligase: ATP dependent, joins Okazaki fragments together

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24
Q

Where does initiation of DNA replication occur in E. coli?

What occurs? (What binds to start initiation?)

A

Occurs at origin (special site, rich in A-T ➡️ easily separated)

dnaA protein binds at origin ➡️ local denaturation of DNA ➡️ 2 replisomes assemble at this site ➡️ bidirectional replication

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25
Q

Where does termination of DNA replication occur in E. coli?

What occurs to cause termination?

A

Special site opposite origin

Terminator utilization substance (tus) binds to DNA ➡️ ➖ helicase & prevents replisome from passing through

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26
Q

Elongation of DNA replication:

What is the leading strand synthesis?

A

1st RNA primer synthesized by primase ➡️ DNA polymerase III synthesized DNA progressively until reaches terminus

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27
Q

Elongation of DNA replication:

What is the lagging strand synthesis?

A

Each Okazaki fragment made & joined to those made previously:

RNA primers w/each Okazaki fragment removed by 5’ to 3’ exonuclease activity of DNA polymerase I (replaces RNA w/DNA) ➡️ nick between Okazaki fragments sealed by DNA ligase

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28
Q

What is the function of single stranded DNA binding proteins in DNA replication?

A

(After DNA helicase unwinds dsDNA): Keeps DNA strands from coming back together

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29
Q

Fidelity of DNA replication: How many errors are made per # of bases?

A

1 error/10^8 bases

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30
Q

What is rolling circle replication used for?

A

Phage DNA replication

Bacterial mating process

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31
Q

What are 4 important characteristics of rolling circle replication?

A

1) primer synthesis not necessary
2) leading strand covalently linked to template
3) Replication can continue for many rounds ➡️ generates concatameric branches
4) leading strand template never separates from circular part of molecule

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32
Q

How is DNA replication in eukaryotes initiated?

A

via extracellular signal (from other cells, usually paracrine)

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33
Q

In eukaryotes, what is required for progression of the cell cycle?

A

Timed activation of cell cycle via cyclin/cdk complexes (via signal transduction)

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34
Q

What 3 “special considerations” occur in eukaryote DNA replication (not in prokaryotes)?

A

1) multiple initiation sites (due to huge chromosome)
2) Histone complexes
3) telomere structures

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35
Q

What are the phases of the cell cycle?

A

G0: senescence ➡️ metabolism done, cell eventually dies (can’t return to cell cycle)
G1 (gap): external signal to replicate is sent to nucleus & protein synthesis enables passage to S phase
S: DNA synthesis
G2 (gap): ⬆️ cell size
M: mitosis (chromosomes & cells divide)

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36
Q

What molecules drive the cell cycle?

What molecules inhibit the cell cycle?

A

➕: oncoproteins

➖: tumor suppressor proteins

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37
Q

Purpose of G1➡️S checkpoint of cell cycle?

A

Check for DNA damage ➡️ if damage detected, cell arrested in G1 and DNA repaired

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38
Q

What protein is important at G1➡️S checkpoint (“guardian of the genome”)?

What are the functions of this protein?

A

p53 (tumor suppressor)

cell cycle arrest
DNA repair
Apoptosis (if DNA damage extensive)
Senescence (if DNA damage extensive)
Autophagy
Metabolic reprogramming
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39
Q

What is metabolic reprogramming? (In relation to p53 & tumor suppression)

A

p53 inhibits glycolysis (needed by cancer cells) ➡️ alpha-ketoglutarate important in hydroxylation reactions

40
Q

Purpose of G2➡️M checkpoint in cell cycle?

A

Check for complete DNA replication ➡️ if not, cell arrested in G2 & DNA replication completed

41
Q

How many replication forks are there in average human chromosome? In Drosophila embryogenesis?

A

Humans: 100-200

Drosophila: 6000

42
Q

Compare histones for the leading versus lagging strand during DNA replication.

A

Histones retained by leading strand barely dissociate

After replication, lagging strand bare (as new histones made & assembled)

43
Q

What type of DNA do histones have ⬆️ affinity for?

A

dsDNA

44
Q

Which is bigger: DNA or histone proteins?

A

DNA much bigger than histones proteins

45
Q

Describe steps of what occurs with nucleosomes during DNA replication.

A

1) nucleosome (histone octamer) unwinds & 2 halves divide
2) Replication fork passes & new DNA strands synthesized
3) both halves of nucleosome attached to same daughter strand (leading) ➡️ recombine
4) new histone octamer will be quickly made and added to other daughter strand (lagging)

46
Q

Describe structure & function of telomeres.

A

Repeated terminal sequences (T & G), w/# of telomere repeats ranging from 20-100 (single celled eukaryotes) to >1500 in mammals

Help stabilize chromosome

47
Q

Why would chromosomes become shorter with each round of replication without telomerase?

A

RNA primers at 5’ removed by polymerase alpha ➡️ cannot fill gap because no 3’ OH group present

48
Q

What is the short RNA sequence which telomerase carries?

A

AUC-CCA-AUC

49
Q

Compare telomerase activity of normal somatic cells versus germ-line (stem) cells.

A

Somatic: lack telomerase activity ➡️ chromosome shortening to senescence/cell death

Germ-line: telomerase extends 5’ end of lagging strand ➡️ cells have long life span/immortal

50
Q

What disease does telomerase contribute to? How may this potentially impact treatment of this disease?

A

Contributes to immortality of cancer cells

Anti-telomerase drugs being investigated to treat cancer

51
Q

What is responsible for this action in (1) prokaryotes versus (2) eukaryotes during DNA replication?

Inducing (➖) supercoils ahead of replication fork

A

1) pro: gyrase

2) euk: nucleosome unwinding

52
Q

What is responsible for this action in (1) prokaryotes versus (2) eukaryotes during DNA replication?

Unwinds dsDNA ➕supercoils

A

Both pro & euk: helicase

53
Q

What is responsible for this action in (1) prokaryotes versus (2) eukaryotes during DNA replication?

Adds RNA primers at start of Okazaki fragments at 5’ end

A

1) pro: primase

2) euk: primase subunit of DNA polymerase alpha

54
Q

What is responsible for this action in (1) prokaryotes versus (2) eukaryotes during DNA replication?

Polymerizes leading & lagging strands 5’ ➡️ 3’

A

1) pro: DNA polymerase III

2) euk: DNA polymerase delta, DNA polymerase alpha

55
Q

What is responsible for this action in (1) prokaryotes versus (2) eukaryotes during DNA replication?

Exonuclease removes primers & fills in DNA gaps

A

1) pro: DNA polymerase I

2) euk: DNA polymerase beta, assisted by DNA polymerase alpha

56
Q

What is responsible for this action in (1) prokaryotes versus (2) eukaryotes during DNA replication?

Links Okazaki fragments

A

Both pro & euk: Ligase

57
Q

What is responsible for this action in (1) prokaryotes versus (2) eukaryotes during DNA replication?

Extends 3’ ends of DNA strands
Fills in complementary strand of telomere

A

1) pro: not necessary (circular DNA)

2) euk: telomerase, DNA polymerase alpha

58
Q

What are the 3 main classes of inhibitors of DNA replication?

A

1) prevent/reduce synthesis of precursors (bases, nucleotides)
2) affect either template or priming ability of growing strand
3) act directly on polymerases or other enzymes needed for replication

59
Q

What do intercalating agents do to DNA?

A

1) Induce unwinding, lengthening, & stiffening of DNA double helix
2) Inhibits binding of enzymes (DNA/RNA polymerases, topoisomerase)
3) induce mutations during DNA replication ➡️ ➖ cell division

60
Q

Examples of intercalating agents?

A

Acridines
Ethidium bromide
Actinomycin D
Anthracyclines (daunomycin, doxorubicin, epirubicin, idarubicin)

61
Q

What agents covalently bind to DNA ➡️ cause chain breakage?

A

Bleomycin

Zinostatin

62
Q

What agents cause cross-linking of DNA strands?

A

Alkyl sulphonates
Anthramycin
Mitomycin
Nitrogen mustards

63
Q

What compounds bind to guanine ➡️ ➖ DNA expression?

A

Platinum & gold coordination compounds

64
Q

What agents prevent extension of growing DNA chain?

A

2’,3’-dideoxyribonucleosides

cordycepin

65
Q

agents which act on & inhibit DNA polymerases:

Acyclovir: specific inhibition?

A

inhibits DNA polymerase of HSV

66
Q

agents which act on & inhibit DNA polymerases:

Aphidicolin: specific inhibition?

A

Inhibits DNA polymerase alpha & delta

67
Q

agents which act on & inhibit DNA polymerases:

2’-dideoxyazidocytidine: specific inhibition?

A

Inhibits bacterial primase

68
Q

agents which act on & inhibit DNA polymerases:

Which agents inhibit DNA gyrase in bacteria?

A

Coumermycin
Novobiocin
Oxolinic acid
Nalidixic acid

69
Q

What is the function of topoisomerase I?

A

Relieves torsional stress in DNA by inducing reversible single strand break (no energy required) ➡️ essential in DNA replication & cell growth

70
Q

What do topoisomerase inhibitors do?

Example?

A

Produce double strand breaks in DNA that are irreversible ➡️ leads to cell death

Camptothecins

71
Q

What two things contribute to genetic stability?

A

1) highly accurate DNA replication system

2) DNA repair system when DNA damaged

72
Q

What is a mutation?

A

Any change in genetic material or base sequence of DNA

73
Q

Compare somatic mutations to germ-line mutations.

A

Somatic: cell changes = mostly deleterious for affected individual

Germ-line: heritable or stable changes ➡️ lead to evolution, new species

74
Q

At what rate (rate/cell cycle) do mutations continuously occur?

A

1 mutation / 10^9 base pairs

75
Q

Small scale mutations: single/a few base changes

Types?

A

1) Base substitution: transition, transversion (based on base change); silent, missense, nonsense (based on consequence)
2) Base deletion
3) Base insertion

76
Q

Large scale mutations: chromosomal mutations

Translocations?

A

Interchange of large segments of DNA

77
Q

Large scale mutations: chromosomal mutations

Inversions?

A

Region of DNA flips its orientation w/respect to rest of chromosome

78
Q

Large scale mutations: chromosomal mutations

Deletion?

A

Loss of important genes

79
Q

Large scale mutations: chromosomal mutations

Nondisjunction?

A

Lost track of where they are supposed to go in cell division

80
Q

What base changes = transition?

What base changes = transversion?

A

Transition = purine ➡️ purine (A ↔️ G) or pyrimidine ➡️ pyrimidine (C ↔️ T)

Transversion = purine ↔️ pyrimidine (A ↔️ C , A ↔️ T, G ↔️C, G ↔️ T)

81
Q

What occurs in silent mutations? Missense? Nonsense?

A

1) Silent: no amino acid change
2) Missense: amino acid change
3) Nonsense: introduces new stop codon ➡️ termination of protein synthesis

82
Q

Insertions & deletions may cause what?

A

Codon frame shifts: changes reading frame of base sequence of gene ➡️ synthesis of completely different protein

3 base insertions or deletions do not change reading frame but may cause diseases: fragile X syndrome (CGG repeat ➡️ mental retardation), Huntington’s disease (CAG repeat ➡️ chorea, dementia, death)

83
Q

What is a mutagen?

A

Physical/chemical agent that causes mutations

84
Q

What is mutagenesis?

A

Process of producing a mutation (induced or spontaneous)

85
Q

What mutations do chemical mutagens cause?

A

Modification of bases (alkylation)

Insertion between bases

86
Q

What mutations does UV & ionizing radiation cause?

A

Cross-linking of base pairs
Ring opening
DNA strand breaks

87
Q

What is the Ames test?

A

Determines if a chemical is a mutagen

Assumption: any substance that is mutagenic may also be a carcinogen (cause cancer)

88
Q

Types of DNA damage:

Base loss?

A

Base lost but sugar-P backbone intact ➡️ strand can’t replicate if not repaired

89
Q

Types of DNA damage:

Base modification?

A

1) Deamination of cytosine ➡️ uracil
2) chemical modification: ROS and environmental chemicals can modify bases via alkylation
3) photodamage (UV) ➡️ thymine dimers

90
Q

Types of DNA damage:

Replication errors?

A

During DNA replication: mismatch, insertion, deletion

91
Q

Types of DNA damage:

Inter-strand cross links?

A

Crosslinks formed via bifunctional alkylating agents, UV, ionizing radiation

92
Q

Types of DNA damage:

DNA-protein crosslinks?

A

Crosslinks between DNA strands & protein molecules formed via bifunctional alkylating agents, UV, ionizing radiation

93
Q

Types of DNA damage:

Strand breaks?

A

ss nicks and ds breaks via ionizing radiation

94
Q

Types of DNA repair:

Direct reversal of damage: 3 examples?

A

1) Light induced (300-600 nm) enzymatic cleavage of T, C, and CT dimers via photolyase (does not occur in placental mammals)
2) O6-methyl-guanine-DNA-methyltransferase: O6-methyl group transferred from DNA ➡️ Cys of enzyme
3) DNA ligase seals nicks

95
Q

Types of DNA repair:

Excision repair + replacement with new DNA: 3 types? (In both pro & euk)

A

1) mismatch repair
2) base excision repair
3) nucleotide excision repair

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