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MBM > DNA Repair > Flashcards

DNA Repair Flashcards

1
Q

How often is DNA being damaged and repaired?

A
  • constantly being repaired in normal healthy cells to restore normal sequence
  • up to 500,000 DNA modification events per day
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2
Q

What kinds of things does the DNA face that can damage it?

A

endogenous- inside source (reactive oxygen, thermal changes, metabolism)

exogenous- outside source (chemicals, irradiation, UV light, x rays)

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3
Q

When does a mutation result? vs healthy cell?

A
  • when the rate of damage exceeds the rate of repair

- when rate of damage equals rate of repair = healthy

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4
Q

Are all mutations bad?

A

no because some lead genetic variation which drives evolutionary change

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5
Q

Mutations in germ cells cause what? somatic cells?

A
  • germ- heritable genetic disorders

- somatic- acquired diseases such as cancer or neurodegenerative disorders

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6
Q

T/F

Polymerase error is major source of DNA damage.

A

False

minor

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7
Q

What are three types of DNA damage?

A
  1. depurination
  2. deamination
  3. oxidative damage to nucleotides
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8
Q

What is depurination? How many times does this happen per day?

A
  • spontaneous loss of adenine or guanine nitrogenous base

- 5,000 per cell per day

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9
Q

What is deamination? How many times does this happen per day?

A
  • common spontaneous loss of NH2
  • results in unusual bases not usually found in DNA
  • 100 per cell per day
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10
Q

What happens in oxidative damage to nucleotides?

A
  • over 80 types of base damage due to reactive oxygen species
  • 8 hydroxyguanine (8-oxoG)
  • base pairs with A instead of C
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11
Q

What makes recognition and repair of deaminated bases easier?

A

the nucleotides formed are not normally present in DNA

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12
Q

What does the deamination of methyl cytosine turn into? Why is this significant?

A
  • thymine
  • it is a normal nucleotide so it is difficult for the cell to recognize it as damage
  • this is why CpG are underrepresented in the genome
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13
Q

Deaminated adenine?

A

hypoxanthine

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14
Q

Deaminated guanine?

A

xanthine

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15
Q

Deaminated cytosine?

A

uracil

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16
Q

Does thymine get deaminated? why?

A

no amine group

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17
Q

What property of DNA makes it ideally suited for repair?

A

double stranded structure

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18
Q

How many different proteins are involved in DNA repair?

A

over 100 different proteins

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19
Q

What are the 5 major pathways for DNA repair?

A
  1. Mismatch Repair (MMR)
  2. Base Excision Repair (BER)
  3. Nucleotide Excision Repair (NER)
  4. Homologous Recombination (HR)
  5. Non-homologous end joining (NHEJ)
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20
Q

Replication error is what type of damage (endo or exo)? What mutations can this lead to? What type of repair is used to fix it?

A
  • endogenous
  • base mismatches, insertion/deletion loops
  • fixed by mismatch repair (MMR)
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21
Q

Problems in the cell environment is what type of damage (endo or exo)? What mutations can this lead to? What type of repair is used to fix it?

A
  • endogenous
  • spontaneous deamination, depurination, oxidation
  • fixed by Base excision repair (BER)
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22
Q

UV exposure is what type of damage (endo or exo)? What mutations can this lead to? What type of repair is used to fix it?

A
  • exogenous
  • cyclobutane pyrimidine dimers, 6-4 photoproducts
  • fixed by photo reactivation, nucleotide excision repair (NER)
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23
Q

ionizing radiation is what type of damage (endo or exo)? What mutations can this lead to? What type of repair is used to fix it?

A
  • exogenous
  • single and double strand breaks, oxidation
  • fixed by double strand break repair, BER
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24
Q

Chemical exposure is what type of damage (endo or exo)? What mutations can this lead to? What type of repair is used to fix it?

A
  • exogenous
  • alkylation, interstrand crosslinks
  • fixed by alkyl transferases, recombination repair
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25
Q

Mismatch repair (MMR) reduces error rate by how much? What type of damage does it repair? What is it important for?

A
  • 100 times
  • repairs polymerase error and small insertions nd deletions
  • important for stability of micro satellites
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26
Q

Mutation of MMR enzymes is associated with what diseases?

A
  • inherited colorectal cancer
  • lynch syndrome
  • HNPCC
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27
Q

What is the process of MMR? What is strand selection based on?

A
  • proteins (MutS and MutL) scan for small structural distortions
  • strand selection based on nicks in newly synthesized strand
  • area between mismatch and nick is excised
  • DNA pol fills gap
  • DNA ligase seals nick
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28
Q

What is the biggest challenge for MMR?

A

making sure it repairs the correct strand, newly synthesized

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29
Q

What is the most common type of repair in human cells? what are the subtypes?

A

-excision repair:

  • base excision repair (BER)
  • nucleotide excision repair (NER)
  • transcription coupled repair (TCR)
  • global genome repair (GGR)
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30
Q

What are the basic steps in excision repair?

A
  • recognize damage
  • remove damage by excising part of the damaged strand
  • fill in gap, using the other strand as template
  • ligate to seal nicks
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31
Q

What are DNA glycosylases in BER? what types of damage do they recognize? What do they catalyze?

A

-family of enzymes that recognize specific types of damaged nitrogenous bases

  • deaminated C’s, A’s
  • alkylated or oxidized bases
  • bases with opened rings
  • bases with reduced double bonds

-catalyze the removal of the damaged nitrogenous base by hydrolysis of the N-glycosidic bond

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32
Q

What is the process of Base excision repair (BER)?

A
  • damage to nitrogenous base portion of a nucleotide
  • glycosylase removes base, backbone intact
  • AP endonuclease cuts backbone 5’ of AP (apurinic) site
  • AP lyase (phosphodiesterase) removes sugar by cutting 3’ of AP site
  • DNA pol fills gap
  • Ligase seals nicks

-AP sites from depurination fixed this way, but starts after glycosylase step

33
Q

What type of damage does NER fix compared to BER?

A
  • damage involves entire nucleotide, larger structural distortion
  • covalent attachment of large hydrocarbons
  • pyrimidine dimers- covalent bonds between pyrimidines, caused by UV damage
34
Q

What is the process of NER?

A
  • Excision nuclease (endonuclease) makes a double excision surrounding the damage
  • DNA helices (TFIIH) removes the damaged section
  • DNA pol fills gap
  • DNA ligase seals nicks
35
Q

What are the subtypes of NER?

A
  • transcription coupled repair (TCR)

- global genome repair (GGR)

36
Q

What does TCR repair? What triggers it?

A
  • removes lesions from transcribed regions of DNA

- triggered by stalled RNA pol

37
Q

What does GGR repair? It is decreased in what?

A
  • removes lesions all over genome

- decreased in terminally differentiated cells

38
Q

When do double strand breaks occur? What can this type of damage lead to? What repairs double strand breaks?

A
  • happen in every S phase
  • can also be caused by ionizing radiation or oxidizing agents
  • damage leads to chromosomal translocations or cell death if not repaired
  • repaired by homologous recombination (HR) or non-homologous end joining (NHEJ)
  • DNA fragments joined could be broken ends of same chromosome, or ends of 2 chromosomes
39
Q

Non homologous end joining (NHEJ) is the dominant mechanism in what phase? why?

A
  • G1 after mitosis
  • there are no sister chromatids available in G
  • quick and dirty mechanism
40
Q

What is the process of NHEJ?

A
  • ends bound by Ku, kinase, and nuclease (artemis)
  • Po4- kinase unwinds the DNA
  • ends anneal via short region with compatible sequence
  • ends trimmed, extended as needed, then ligated
41
Q

Why is NHEJ known as the error prone mechanism?

A
  • several base pairs at the site of the break are frequently removed
  • some DNA is deleted, but some DNA has already been lost from the double strand break
  • repairing the break is more important than losing a few more nucleotides, especially if caused by ionizing radiation
42
Q

The DNA fragments joined in NHEJ could come from what?

A

the same chromosome or the ends of 2 different chromosomes

43
Q

Homologous recombination (HR) is the dominant mechanism in what phase? What is HR? Why is it essential? What else is it involved in? Precise mechanism?

A
  • used for repair of double stranded breaks in S and G2 when sister chromatids are available, before cell has divided, mitosis
  • HR is the genetic exchange between a pair of homologous DNA sequences, usually two copies of the same chromosome
  • essential for every proliferating cell to restart stalled replication forks
  • also involved in crossing over of chromosomes in meiosis- resolution of join molecule is different
  • cleavage and rejoining are precise, no nucleotides lost or gained
44
Q

How does the resolution of the joint molecule differ in mitosis vs meiosis?

A

mitosis repair pathway does not result in crossover, but meiosis does which increases genetic diversity

45
Q

what type of junction forms in HR in meiosis?

A

holliday

46
Q

What is the process of HR after a double strand break?

A
  • nuclease digest 5’ ends of broken strands
  • strand exchange by complementary base pairing
  • repair polymerase synthesizes DNA using undamaged DNA as template, strand invades
  • invading strand released, broken double helix reformed
  • DNA synthesis continues using strands from damaged DNA as template
  • DNA ligation
47
Q

What does HR require to happen?

A
  • homolgous sequences
  • strand invasion and exchange
  • strand elongation
  • cleavage and ligation
48
Q

What are Brca 1 and Brca 2 involved in? Mutations of these are found where?

A
  • involved in formation of joint molecules in HR, may be involved in NER and NHEJ
  • mutated in inherited breast and ovarian cancer
49
Q

How does a replication fork break? What repairs broken replication forks?

A
  • if a replication fork reaches a single strand break, it collapses
  • HR can be used to repair the fork using the newly synthesized DNA from the other strand
50
Q

What is the process of repairing a broken replication fork?

A
  • replication moves until it reaches a nick, then it breaks
  • nuclease degrades 5’ end of broken strand
  • strand exchange, DNA synthesis
  • strand breakage, more DNA synthesis
  • replication fork restarts
51
Q

What is xeroderma pigmentosum? What causes it? Risk of cancer?

A
  • rare autosomal recessive disorder
  • defective NER causes failure to repair UV damage
  • 1000X increased risk of cancer in cutaneous basal and squamous cell carcinomas
  • increased risk of internal cancer by age 20
52
Q

What helped to identify proteins involved in pathway for xeroderma pigmentosum?

A
  • locus heterogeneity

- 7 complement groups (one group has proteins that another group doesn’t have) compared proteins

53
Q

What is the mutator phenotype?

A

mutations in proteins involved in cell growth eventually result in loss of cell cycle control

54
Q

What are the caretaker proteins? why?

A

DNA repair proteins because they can be considered tumor suppressor proteins, repairing DNA before cancer takes over

55
Q

what can faulty DNA repair mechanisms result in?

A

double strand breaks -> chromosomal rearrangements -> mutator phenotype -> mutation of tumor suppressor genes or oncogenes -> loss of cell cycle control checkpoints and progression -> genomic instability -> cancer

56
Q

What is the process of chromosome breakage fusion bridge cycle?

A
  1. cell enters S phase and replicates its DNA despite unprepared strand break
  2. one daughter cell inherits a chromosome lacking a telomere
  3. cell enters S phase and replicates DNA
  4. sister chromatid ends that lack telomere fuse together
  5. fused sister chromatids are pulled apart at mitosis, creating breakage at a new sit
  6. one daughter cell inherits a chromosome with duplicated genes but again lacking a telomere
  7. cycle repeats
57
Q

How do cells normally treat a loss of telomeric DNA?

A
  • similar to double strand breaks
  • cell cycle checkpoints are activated, repair pathway stimulated
  • if too much to repair, cell becomes senescent and dies
58
Q

What is the consequence of the chromosome breakage fusion bridge cycle? why does this happen?

A
  • checkpoints fail, cell continues to proliferate
  • continues to lose telomeric DNA until telomeres are not functional
  • chromosomes fuse together and undergo the cycle
  • most of the time the cell dies due to genomic instability
  • sometime rearrangements reactivate telomerase and chromosomes are stabilized
  • cell survives but has many mutations
59
Q

What can the reactivation of telomerase do?

A

restored ends of DNA and make the cell immortal, cancer

60
Q

What are micro satellites? Where are they found?

A
  • simple sequence repeats
  • short, tandem repeats of 1-6 nucleotides
  • most abundant class of repetitive DNA
  • scattered throughout genome, more frequent in non coding regions
  • presents challenges to replication and repair mechanisms
61
Q

What are expansion of trinucleotide repeats known as?What do they cause? What does the mechanism of disease depend on?

A
  • dynamic mutations
  • at least 20 neurological or neuromuscular disorders are caused by them
  • depends on location of repeats within the gene, and function of affected protein
62
Q

What is the genetic anticipation of expansion of trinucleotide repeats?

A
  • increased odds of inheriting
  • decreased age on onset
  • increased severity in later generations
63
Q

What repeated sequence create stronger pairs?

A

CG sequences

64
Q

What diseases result from trinucleotide expansions in non-coding sequences? large changes in repeat number are associated with what?

A
  • Fragile X
  • Freidrich ataxia
  • spinocerebellar ataxias type 8 and 12
  • myotonic dystrophy

-maternal transmission

65
Q

What are two disease causing mechanism for trinucleotide expansion in non-coding sequences?

A
  1. decreased transcription due to changes in chromatin structure or increased methylation (fragile X)
  2. RNA gain of function- abnormal interaction of RNA with proteins involved in mRNA processing (myotonic dystrophy)
66
Q

What diseases result from trinucleotide expansions in exonic repeats (polyglutamine diseases)? What are they due to? large changes in repeat number are associated with what?

A
  • huntingtons disease
  • spinobulbar muscular atrophy
  • spinocerebellar ataxias types 1, 2, 3, 6, 7
  • due to expansion of CAG- glutamine
  • paternal transmission
67
Q

What is the disease causing mechanism for trinucleotide expansion in exonic repeats?

A

toxic gain of function of mutant protein

68
Q

What are the two models of trinucleotide expansion hypothesis?

A
  1. slippage of newly synthesized strand during rapid replication
  2. Recombination
    - could be happening at same time
69
Q

Hypothesis of slippage in expansion?

A
  • primary hypothesis
  • repeats tend to form hairpin structures in newly replicated lagging strand
  • pulls polymerase back so it copies the same area twice
  • should be repaired by MMR, but structural features of repetitive DNA make this more difficult
70
Q

Hypothesis of recombination in expansion?

A
  • repetitive sequences are recombinogenic

- expansion can result due to unequal cross over and to polymerase slippage during repair of DNA synthesis

71
Q

How many loci are unstable in an unstable micro satellite (MSI+)? what cancers result? what causes micro satellite instability and cancers? Can it be inherited? what else?

A
  • at least 2 out of 5
  • occurs in 15% of all colorectal cancers
  • also in ovarian, endometrial, skin, brain, stomach cancers

-caused by defects in MMR system

  • inherited in lynch syndrome, HNPCC
  • somatic mutation
  • methylation of gene encoding MMR proteins
72
Q

Affected micro satellites (tumors) are usually what type of cells?

A
  • diploid
  • rarely show loss of genetic material or loss of heterozygosity
  • improved prognosis
73
Q

Do tumors respond the same to chemotherapy and/or radiotherapy?

A
  • no

- 5 fluorouracil selectively kills with MMR system intact, no survival benefit for patients with MSI-H tumors

74
Q

How are MSI (micro satellites) and TNR (trinucleotide repeats) separate but related?

A

MSI- lynch syndrome/HNPCC, micro satellite changes throughout genome are not repaired due to mutations in MMR proteins

TNR- huntingtons, the secondary structure of DNA in a specific gene causes failure of MMR to repair expansion

75
Q

Where are CpG islands normally found? Are they methylated? What are abnormal methylation patterns in cancer?

A
  • found in promoters, not methylated
  • most CpG in other areas of genome are methylated
  • overally hypomethylation
  • hypermethylation of CpG islands in promoters
76
Q

Hypermethylation of CpG islands is associated with what?

A
  • abnormal gene silencing
  • recruitment of histone deacetylases (HDAC)
  • inhibition of transcription
  • inactivation of tumor suppressor genes or caretaker genes
77
Q

global hypomethylation results in what? What does this cause?

A
  • loss of imprinting (LOI)

- causes imprinted genes to be over expressed by expressing both alleles so twice as much protein is made

78
Q

Is methylation responsible for inherited cancer syndromes? Why?

A

no because methylation patterns are erased in the germ line cells

79
Q

How can methylation be involved in sporadic cancers or the 2nd hit of inherited cancers? CIMP?

A
  • methylation of a tumor suppressor could be second hit by inactivating normal allele in a somatic cell
  • CIMP- CpG island methylator phenotype characterized by promoter hypermethylation (present in 18% of colorectal cancers)

MBM (24 decks)

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