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PA Biochem > L22: DNA replication, mutation, and repair > Flashcards

L22: DNA replication, mutation, and repair Flashcards

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1
Q

What is a genome and it’s primary function

A

complete set of genetic material

46 chromosomes

contains full set of INFORMATION to make human

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2
Q

Human cells are…

A

Diploid 2 – 2 copies of each chromosome

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3
Q

Define DNA

A

physical support of genomic information

Polymer of nucleotides

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4
Q

The DNA double helix is what?

A

Directional (5 to 3) and antiparallel

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5
Q

Explain ploidy change during cell cycle

A

After mitosis = 2n

During S phase, after DNA replication = 4n

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6
Q

Semi-conservative DNA replication

A

two new copies – one template (parental) and one new complementary strand

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7
Q

What happens to parental strands during DNA replication?

A

They are separated

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8
Q

What are origins of replication?

A

Opening of double helix (where the parental strands are unwinded)

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9
Q

What are the openings of origins of replication performed by?

A

MCM DNA helicase

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10
Q

What is the bidirectional forks?

A

Translocation of DNA helicases toward 5’ end of each strand (opposite directions)

Giving replicated genome (2 template strands)

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11
Q

3 properties of DNA polymerase

A
  1. unidirectionality of DNA sythesis from 5’ to 3’
  2. Require RNA/DNA primers
  3. Proofreading activity (3’ to 5’ exonuclease)
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12
Q

What are primers?

A

Short RNA sequence complementary to DNA template – initiation of DNA replication

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13
Q

What is the leading strand

A

3’-5’ relative to the replication fork

continuous DNA syth of complementary strand

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14
Q

Lagging strand

A

5’-3’ relative to replication fork

continuous synth is NOT possible

short fragments called Okazaki

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15
Q

What strand are the Okazaki fragements a part of?

A

Lagging

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16
Q

Role of DNA primase?

A

Sythesis of RNA primers

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17
Q

Role of DNA ligase

A

Join the Okazaki fragments

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18
Q

Role of DNA topoisomerase

A

Release tension in DNA upstream of the replication fork

relaxing the supercoiling

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19
Q

Does DNA polymerase remove the RNA primer?

A

Yes

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20
Q

What are telomeres? What happens at each cell division

A

Repetitive DNA sequence at the end of chromosomes – protection against degredation/wrong joining

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21
Q

Where does the end replication problem occur? why?

A

telomeres

bc DNA polymerase cannot replicate 3’ end of lagging strand –> nucleotides lost –> telomere shortening

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22
Q

What happens to telomeres/cell after a critical limit?

A

Telomeres are gone –> senescence (cell division stops + death)

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23
Q

Role of telomerase? Where is this enzyme?

A

Prevents telomere shortening expressed in immortal cell types (need repeated cell division)

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24
Q

Example of cells that have telomerase

A

Embryonic stem, adult stem, male germ

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25
What is the potential target for cancer therapies in terms of their immortality?
telomerase
26
4 types of DNA replication inhibitors
1. inhibition of DNA polymerase 2. Inhibition of precursor sythesis 3. Inhibitors of DNA topoisomerases 4. inhibition of replication fork
27
Importance of replication inhibitors -- medications
Anti-cancer drugs Anti-viral drugs Antibiotics
28
List the types of small scale mutations
Point (Silent, missense, nonsense) Indels (Insert/deletion) ex: cystic fibrosis CTFR gene
29
Name the 4 types of Large scale mutations
1. Micro-macro deletion 2. Duplications 3. Translocation 4. Inversion
30
What does basal mutation rate refer to?
the incidence of new mutiations that go unrepaired by DNA polymerase proofreading and DNA repair mechanisms
31
What leads to mutations
Urepaired and cumulative DNA damage
32
Are mutations rare
Yes
33
Describe point mutations & the types
deletion/substitution at a single base pair Ex: Silent/missense/Nonsense
34
What is a mutant DNA sequence effect
Change in the amino acid
35
What is a nonsense mutation
Results in a stop codon
36
Explain insertion/deletion + effects
indels not divisible by 3 lead to a frame shift mutation insertion of 3 = no frameshift and either a mutant AA sequence
37
What does a frameshift mutation cause?
change in codon reading frame typically result in a stop codon
38
Explain Cystic Fibrosis mutation
point mutation and indels in CFTR gene Many get the F508 mutation -> delete 3 nucleotides from CFTR protein
39
Examples of ionizing radiation
x-ray, gamma rays (high energy)
40
How does ionizing radiation damage DNA?
directly by **breaking chemical bonds** indirectly by generating **reactive oxygen species(ROS)** causing strand breaks + modifications
41
How does non ionizing radiation effect DNA? Example?
Most common = **UV light** Induces covalent bonds between pyrimidine bases (DNA helix distorted) **ss breaks** Also does **ROS** damage
42
What are genotoxins?
Chemical agents that damage DNA
43
How do genotoxins affect DNA
Direct or indirect **intercalation, base crosslinking, ROS**
44
Examples of genotoxins
PAH, formaldehyde, heavy metals
45
In human disease what is a large scale mutation
Chromosomal rearrangements from a few kb to a whole chromosome
46
Explain macro/micro deletion
Removal of large regions on chromosome DNA --> loss of function
47
Explain duplication
Repitition -- extra copies of DNA AKA copy number variation (CNV)
48
Explain translocation
exchange of large DNA sequence from one chromosome to another Reciprocal and can cause aberrant gene fusions
49
Explain inversion
Excision/reversion of orientation of chromosome fragment --> gene fusion
50
Explain the Philadelphia chromosome in human disease
reciprocol translocation between the long arms of chromosomes 9 and 22
51
result of Philadelphia chromosome
short chromosome 22 BCR gene fused with ABL gene --> proliferation Chronic myeloid lukemia, acute lymphoblastic anemia, acute myeloid leukemia
52
Explain charcot-marie-tooth disease
cause by duplication of large region of short arm of chromosome 17
53
result of charcot-marie-tooth disease
Overproduction of PMP22 protein--> myelin sheath not stable Loss of muscle, tissue, and touch
54
3 major consequences of large scale mutations
1. disruption 2. amplification 3. fusion
55
How many repair systems do humans have
4
56
Role of mismatch repair (MMR)
correct replication errors (mismatching of normal bases) MM recognition (MSH2/MSH6/MLH1) Excision (PMS2) Repair/ligation (polymerase, ligase)
57
Disease associated with mutation in MMR (MLH1 MSH2+ 6, PMS2)
Lynch syndrome
58
What is lynch syndrome
hereditary --> non-polyposis colorectal cancer (high lifetime risk of develooping) Deficient MMR -> mutations -> cancer
59
What is BER for?
small DNA lesions not distorting DNA helix
60
Examples of what base excision repair (BER) would repair
spontaneous depurination --> loss of A or G base --> result: abasic site (stall rep. fork) Spontaneous deamination --> loss of amine group --> result cystosine -> uracil
61
Explain how BER works
62
Explain how PARP inhibitors work in cancer treatments
Block PARP -> cancer cells cannot repair themselves *medications ending in -parib*
63
When is nucleotide excision repair used?
Bulky DNA lesions - block DNA replication
64
2 main sources of bulky DNA lesions
UV light --> form pyrimidine-pyrimidine dimers --> distort helix intercalating genotoxins (PAH) --> bulky adducts --> helix distorted
65
Explain how nucleotide excision repair works?
Bulky DNA lesion -> formation of DNA buble (topoisomerase) --> excision of damaged strain --> Dna polymerization and ligation
66
What is Xerdoderma pigmentosum (XP)?
lose ability to removed UV caused damage from DNA via NER people are sensitive to light induced skin damage
67
What does a double strand break (DSB) involve? what induces it?
Breaking of both strands of the helix induced by ionizing, ROS, stalling rep. fork
68
What are the two pathways of DSB repair?
1. homologous recombination: high fidelity - no loss of DNA 2. non-homologous end joining: errorprone - loss of DNA
69
When is homologous recombinant typically used?
S and G2 phase
70
Explain how homologous recombination works
71
What important roles in homologous recombination(HR)?
BRCA1 --> recognize DSB, end resection, recruit repair proteins BRCA 2 --> homologous pairing and strand invasion
72
How does PARP inhibitor work with BRCA1/2 cancers?
BRAC1/2 cancer cells are HR deficient + inhibition of BER = cell death
73
Cancer associated with HR pathology?
Breast cancer
74
What does non-homologous end joining repair do?
recognize DSB --> ligates the end of broken DNA (phosphorylation and ligation)
75
NHEJ cons
error prone, potentially mutagenic, loss of DNA

PA Biochem (16 decks)

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