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Cancer Biology T2 > L36 DNA Damage and Repair > Flashcards

L36 DNA Damage and Repair Flashcards

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1
Q

DNA Damage Categories

A
  • spontaneous (endogenous)
  • environment (exogenous)
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2
Q

spontaneous (endogenous)

A
  • arise during DNA rep, division and repair
  • result from alteration in the chemistry of DNA bases (turomeric shifts, deamination of bases; depuination and depyrimidination)
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3
Q

environment (exogenous)

A
  • exposure to chemical mutagens (e.g. alkylating agens, polycyclic aromatic hydrocarbons, aflatoxis)
  • exposure to physical agent mutagens (e.g. UV or ionising radiation)
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4
Q

Polymerase (spontaneous (endogenous) DNA damage)

A
  • normally polymerase can move backward and correct itself if it copies incorrectly
  • ‘proofreading’ ability
  • D400A mutation (in proofreading domain of DNA polymerase) in mice showed poor tumor progression
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5
Q

Mismatch repair (spontaneous (endogenous) DNA damage)

A
  • usually goes back and repairs mistakes from polymerase
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6
Q

DNA replication error frequency

A

DNA polymerases have an incorporation error frequency of 1 in 1000000 copied nucleotides
* 3’ to 5’ proofreading by polymerases reduces this to 1 in 100000000 copied nucleotides
* The mismatch repair system reduces this to
1 in 10000000000 copied nucleotides

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7
Q

DNA strand breaks (spontaneous (endogenous) DNA damage)

A
  • during replication the DNA is vulterable to breakage when the replication fork is made
    estimated 10 strand breaks are formed per cell during S-phase
  • failure to repair can lead to TRANSLOCATION AND CHROMOSOMAL BREAKS
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8
Q

Tautomeric shift (spontaneous (endogenous) DNA damage)

A

When there is alteration to the base pairing
- the hydrogen bonds change
- e.g. Keto (common) and Enol (rare) form OR amine (common) and imine (rare) form

  • the other form can pair with something else
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9
Q

Deamination of DNA bases (spontaneous (endogenous) DNA damage)

A
  • losing amine entities
  • exocyclic amine groups that aren’t part of the carbon ring are lost
  • when this happens, it can result in a different base forming e.g. (cytosine to uracil or adenine to hypoxanthine or guanine to xanthine)
  • it can lead to DNA RECOGNIZING IT AS SOMETHING DIFFERENT (Transition mutation)
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10
Q

DNA Alkylatiohn (Environmental DNA Damage)

A
  • the addition of a methyl or ethyl group to the DNA
  • The guanine N7 and adenine N3 are the major sites
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11
Q

Preferred sites of methylation and why?

A

guanine N7 and adenine N3
- because they are the most electro negative sites in the molecule

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12
Q

monofunctional alkylation

A
  • chemical adds 1 methyl/ethyl group
  • only interacts with 1 site
  • 7 alkylguanine is the major product
    (almost HARMLESS)
  • ## BUT…. 3-alkyadendine (formed less frequently) is very toxic
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13
Q

bifunctional alkylating agents

A
  • can add two methyl/ethyl groups
  • interacts with two nucleophilic sites
  • could produce CROSSLINKS
  • can be interstrand, intrastrand, or DNA protein
  • the crosslinks = a locked strand which BLOCKS THE PATH OF THE POLYMERASE so DNA can’t replicate
  • highly toxic becuase nothing can happen
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14
Q

3-alkyadendine

A
  • monofunctional alkylation
    -DNA minor groove, blocks progression of DNA polyer
  • more rare
  • major toxic alkylation
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15
Q

7 alkylguanine

A

the major product in monofunctional alkylation
- b/c in the major groove, not much change in structure or pairing
- less chance of mutation happening (almost HARMLESS)

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16
Q

O-6 alkylguanine

A
  • formed even less frequently than N7-alkylguanine and N3-alkyladedine
  • base is locked in the enol tautomeric form
  • can base pair with either C or T
  • can result in a G to A transition muation which is critical in carcinogensis
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17
Q

Why is O-6 alkylguanine carcinogenic?

A
  • it can result in a G to A transition muation which is critical in carcinogensis
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18
Q

metabolism of carcinogens

A
  • cytochrome P-450 that is in liver, enzyme that mainly digests
  • compoound is converted to a less toxic form and more easily removable
  • SOMETIMES a harmLESS may be converted to a harmFULL molecule
  • enzymes create a very reactive compound
19
Q

enzyme in liver that digests carcinogens

A

cytochrome P-450

20
Q

alfatoxin B1

A
  • normally not carcinogenic
  • but P-450 in the liver can convert it to a carcinogenic form that reacts with DNA and alkylates them
21
Q

nitrosamines

A
  • found in tobacco
  • linked to adenocarcinoma of ht elung
  • liver changes them to be highly reactive
  • NNN ad NNK are extensively metabolized and when reactive, interact wiht DNA
22
Q

China study showing ___ is a mutagen

A
  • area of china had fungal toxin alfatoxiin B1 made by moulds that grow on peanuts and grains stored improperly
23
Q

UV radiation

A
  • creates covalent crosslinks between adjacent pyrimidine bases in DNA
  • cyclobutane pyrimidine dimers are the major photoproductws
  • more than 60% are TT (thymine dimes), 30% are CT dimers and the rest are CC
  • structures are relatively stable and persist unless they are recognized and repaired (they aren’t easily removed)
24
Q

ionising radiation

A
  • can be direct or indirect (by creation of free radicats)
  • also interact with DNA and cause alkylazing agents
25
Q

DNA damage from ionising radiaiton

A
  • DNA damage (direct or indirect)
  • DNA single and double strand breaks
  • double strand breaks are cytotoxic and difficult to repair
26
Q

oxidation of bases in DNA

A
  • ROS produced by ionising radiaiton = oxidation of DNA bases
  • frequent oxidation reaction
    involves deoxyguaninosine which is
    oxidized to 8-oxo-deoxyguanosine (8
    -oxo-dG).
  • 8-oxo-dG can mispair with
    deoxyadenosine, which can lead to a
    G to T transversion.
27
Q

Methods of DNA damage repair

A
  • Direct reverasal of damage
  • exision of damage
  • double strand break repair
  • damage tolerance (acts like nothing is wrong)
  • cell cycle arrest or cell death
28
Q

PHYTOLYASES - Direct reversal of DNA damage (Methods of DNA damage repair)

A
  • e.g. 1 removal of pyridine dimers by PHOTOREACTIVATION
  • PHYTOLYASES are enxymes that repaire UV damage
  • requrie light, more present in plants/animals and not present in humans
29
Q

O6-methylguanine methyltransferase- Direct reversal of DNA damage (Methods of DNA damage repair)

A
  • repaires O6-methylguanine
  • methyle group transferred from guanine to a cysteine group int he active site of the enzyme
  • BUT A SUICIDE ENZYME- SO ONLY OWORKS ONCE
30
Q

MISMATCH REPAIR (excision of DNA damage)

A

Can repair:
- basebase mismatches e.g. G:T
- one base insert/delete
- 1 base insertion/deletion loops
- recombination intermediates
MUTS and MUTL collaborate to initiate repair of mismatched DNA

31
Q

MUT-S and MUT-L

A
  • heterodimers
  • repair mismatched DNA
  • collaborate together (for each situation a set of 1 S and 1L work together)
32
Q

MUT-S and MUT-L

A
  • heterodimers
  • repair mismatched DNA
  • collaborate together (for each situation a set of 1 S and 1L work together)
33
Q

Base excision repair (excision of DNA damage repair mechanisms)

A

DNA glycosylases initate it by recognizing an abnormal base
- they cleave its bond to deooxyribose
- each DNA glycosylase is specialized to recognize a unique abnormal base

34
Q

Uracil DNA-glycosylase

A
  • base excision repair mechanism
  • recognized uracil and removed
  • base-free site is excised by an apurinic/apyriminic endonuclease (APE)
  • gab is filled by a DNA polymerase and sealed by a DNA ligase
35
Q

Poly-(ADP ribose)polymerase-1 (PARP1)

A
  • DNA repair enzymes involved in base excision
    repair are recruited to single strand breaks by
    the action of PARP1.
  • It binds to the breaks and attaches multiple
    ADP-ribose units to itself and to other proteins.
  • The ADP-ribose chains act as docking sites for
    the repair enzymes.
  • TARGETABLE ENZYME IN TREATMENT
36
Q

nucleotide excision repair

A
  • In contrast to base excision repair, nucleotide excision
    repair largely repairs lesions created by exogenous agents.
  • It repairs bulky, helix-distorting alterations.
  • Rather than removing a single base, it removes damage-
    containing oligonucleotides from DNA.
  • It is highly conserved and has a broad specificity. * It involves the product of over thirty genes.
  • Transcription factor TFIIH is an essential component.
37
Q

TFIIH

A
  • transcription factor
  • important in nucelotide excision repair
38
Q

subtypes of nucleotide excision repair

A
  • global genomic repair (GGR)
  • Transcription - coupled repair (TCR)
39
Q

Global Genomic Repair (GGR)

A
  • type of nucleotide excision repair
  • repairs ALL regions of the genome
  • requires XPC
  • defective in p53 mutant cells
40
Q

Transcription - coupled repair (TCR)

A
  • type of nucleotide exiciion repair
  • only repairs template strands during transcription
  • requres CSA and CSP and all other nucleotide exision repair proteins except XPC
41
Q

Homology-directed repair (HR)
(Repair of DNA double strand break)

A
  • Occurs during late S and G2
    phases of cell cycle
    – Requires undamaged sister
    chromatid
    – Important components are
    proteins RAD51, BRCA1 and
    BRCA2
    – The process is error free
42
Q

Nonhomologous end joining (NHEJ)
(Repair of DNA double strand break)

A
  • Used when a sister chromatid is
    not available e.g. in G1
    – Has a normal function in V,D,J
    gene rearrangement
    – Important components are
    proteins KU70, KU80 and DNA-
    PK
    – The process is error-prone
43
Q

Tolerance of DNA damage

A
  • As a last resort cells have distinct
    DNA polymerases that can bypass
    some types of DNA damage in a
    process called translesion
    synthesis (TLS).
  • This process is highly error-prone
    due to the high incidence of
    misincorporated bases
44
Q

The role of p53

A

DNA damage can cause a rapid
increase in p53 levels.
* P53 protein undergoes post-
translational modifications and
induces a number of responses. * This can include cell cycle arrest
which can allow time for DNA
repair, and mobilisation of DNA
repair proteins.
* In certain circumstances, it can
also trigger apoptosis.

Cancer Biology T2 (8 decks)

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