DNA Disease- DNA damage

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What are the 2 types of DNA damage?
Spontaneous and Environmental
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What are the 2 main types of spontaneous damage?
Alterations in structure, and Oxidative damage
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What three subcategories of alterations in structure are there?
Tautomeric shifts, deamination and depurination/depyramidination
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What are tautomeric shifts? To form what? Which can...
When any of the bases undergo a spontaneous rearrangement of bonding. Forms tautomers, which can anomalously base pair with eachother
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Amino --> ? , Keto --> ?
Imino (removal of H), Enol (removal of H)
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What forms of guanine and thymine can bp with each other?
Enol forms
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What is deamination?
When the entire amino group is spontaneously removed (and a double bonded oxygen put in its place)
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What type of reaction is this? What is it dependent on?
Hydrolytic- temperature and pH
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What does a) cytosine b) adenine c) guanine d) 5'-methylcytosine convert to?
a) uracil, b) hypo-xanthine c) xanthine d) thymine
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What are purines?
Adenine and Guanine (double hexamers)
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What are pyramidines
Cytosine, Uracil and Thymine (single hexamers)
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What does depurination/depyramidination describe?
Loss of an entire base
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In acidic conditions, loss of which purine is faster? (and how much faster?)
Guanine, 1.5x faster than adenine
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In alkaline conditions, loss of which purine is faster? (and how much faster)
Adenine, 1.5x faster than guanine
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In comparison to purines, how fast is the loss of pyramidines?
1/20th
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What is the mechanism of loss?
Protonation of base, and cleavage of glycosidic bond
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What is oxidative damage?
When ROS's (reactive oxygen species) set up chain reactions until 2 radicals meet.
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Name 4 ROS's...
1) singlet oxygen 2) hydrogen peroxide 3) hydroxyl radicals 4) superoxide anion
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Name three ways that ROS's are generated
1) interaction of IR or long wavelength UV with biological molecules 2) by-product of cellular respiration 3) synthesised by dedicated enzymes in phagocytic cells (NADPH oxidase and myeloperoxides)
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What are the potential implications of ROS's?
Neuronal cell death, heart disease, cancer... linked with age-related degenerative conditions
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What two main defences are there against ROS?
1) enzymes 2) antioxidants
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Give examples of two enzymes in ROS defence and the reactions they catalyse
1) superoxide dismutase (SOD): converts superoxide ion to hydrogen peroxide + o2 by reacting with hydrogen. b) catalse: converts hydrogen peroxide to water and oxygen
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Name three antioxidants
Vitamin C, Vitamin E and uric acid
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What are the two main types of environmental damage?
Via physical agents and chemical agents
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What proportion of cancers are now thought to be caused by environmental factors?
60-90%
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These environmental factors may be carcinogens or mutagens. Define these.
Carcinogens = agents that cause cancer- referring to any substance that can contribute to tumour formation. Mutagen= agents that cause a permanent, heritable change in DNA (mutation). All carcinogens are mutagens, but not all mutagens are carcinogens
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What is a co-carcinogen?
Substance that by itself doesn't cause tumour formation, but when present with a genotoxin, potency of genotoxin is enhanced.
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what is a tumour promoter?
A substance that doesn't cause a tumour on its own, but enhances tumour formation when given after exposure to a mutagen
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What are the two main physical agents of environmental DNA damage?
UV radiation and ionising radiation
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What does UV radiation cause?
Bonds forming between adjacent pyramidines on the same DNA strand due to energy absorbed from UV
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What are most photoproducts induced by?
UV-C, but also UV-B
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What are the most toxic photoproducts produced? How?
Cyclobutane Pyramidine Dimers (CPDs) (more frequent) and Pyramidine-Pyramidine photoproducts (6-4PPs). By bond formation between adjacent pyramidines
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Describe CPDs and bend created
Double bond formed between carbons of position 5 and 6... therefore pulling adjacent pyramidines closer together and resulting in a 7-9 degree bend
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Name the types of CPDs in order of frequency of occurrence
T-T, C-T, T-C, and C-C
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Describe 4-6PPs
single covalent bond formed between carbons at 6 position of one and 4 position of adjacent on 3' side, creating a 44 degree bend.
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In the T-C 6-4PP, what happens to the amino group from cytosine?
It goes from the 4 position of C to the 5 position of T
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Name the types of 4,6-PPs in order of frequency of occurrence
T-C, C-C, T-T, C-T
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Name four sources of IR.
X-rays, nuclear fallout, cosmic rays, radon
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What does it cause damage to?
All cellular components (unlike UV)
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What are two types of IR damage?
Direct (directly interacts with DNA) or indirect (formation of hydroxyl radicals which then interact with DNA)
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How much of damage from IR is due to water-radiolysis? What does this form?
80%, ROS's and other radical species
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Of this damage, how much is due to the hydroxyl radical? And the rest?
65%, other 15% due to other radicals and ROS's
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What does IR cause? This is similar to what?
Cross-linking of DNA-protein, base damage, and dimerisation. Similar to oxidative damage.
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What is the difference between this and oxidative damage? What can this cause?
IR has the capability to deposit multiple reactive species within the same DNA locale- hence producing many, closely spaced damage sites on both DNA strands. This can cause double-strand breaks, as well as clustered base damages (Much harder to fix)
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What are the 5 types of Chemical agents that cause DNA damage?
1) alkylating agents 2) psoralens 3) electrophilic reactant metabolites 4) benzo[a]pyrene activation 5) Aflatoxins
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Alkylating agents function because they are ____philic with high affinity for ______ centres of organic macromolecules
Electrophilic. Nucleophilic.
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What two types of alkylating agents are there?
mono functional (single reactive grip that interacts with single DNA site) and bifunctional ( 2 reactive groups that interact with 2 sites on DNA)
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What end result do alkylating agents achieve?
disruption of DNA function and cell death
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Name 4 biomolecules that they react with
Water, thiols, amino acids and phosphates
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What two mechanisms can they do this by?
1) replacing H with R (adding alkyl groups to electronegative groups) 2) formation of cross-bridges between 2 guanines (same strand/opposite strands) by bifunctional alkylating agent, (prevents separation of DNA 4 synthesis (i.e. cross-linking agent)
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What is the cross-linking function of alkylating agents exploited by?
Cancer therapy, in designing current chemotherapeutic drugs e.g. cisplatin and carboplatin (stops tumour growth)
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What configuration do psoralens have?
Planar, tricyclic (flat ring structure that can slip between bases)
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What could they be described as?
Photosensitising furocoumarins/furanocoumarins
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What do they do?
form covalent adducts to pyramiding bases on DNA
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Triggered by?
photo reactivation with long wavelength UV radiation (330nm)
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What does this lead to?
DNA crosslinks, distortion and unwinding of DNA.
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Where are psoralens found? What can they cause?
In many vegetables, contact phytophotodermatitis, but not when taken orally
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What happens to electrophilic reactant metabolites?
They undergo a metabolic conversion into reactive mutagens/carcinogens
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What are they converted by? give an example
Metabolic enzymes in the liver e.g. cytochrome P-450 systems
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Why can they produce tumours at sites remote from site of administration?
They're water soluble
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Give two examples
Butter yellow = a liver carcinogen , AAF (N-2-acetyl-2-aminogluorene) = a non-reactive aromatic amine converted to a reactive alkylating agent by liver enzymes (reacts with C8 and N2 on nucleic acids (forming adducts).
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What are benzo[a]pyrenes?
Polycycle aromatic hydrocarbons (PAHs). They are one of the most highly carcinogenic compounds known.
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How does the activation of bento[a]pyrenes occur?
Unmodified, it intercalates between double stranded DNA OR metabolised by liver enzymes to form excitable products or potent epoxides that covalently bind amino group of guanine
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Name 4 sources of bento[a]pyrene exposure.
1) smoke from fireplaces 2) chargrilled meat/fish 3) smoking tobacco 4) inhaling vehicle fumes
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What are aflatoxins?
A naturall occuring myotxin produced by aspergillus flavus or A parasitic (mould types)
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How many types are produced in nature?
Over 13
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What is the most toxic of these?
b1
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Name 5 sources.
1) figs 2) corn 3) peanuts/nuts 4) milk/cheese (through contaminated animal feed)
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How do they act?
They are oxidised by oxygenases of cytochrome p-450 enzymes in the liver to form an epoxide of the compound, which attacks bases (mostly guanine) in ds DNA to form adducts
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What is an adduct?
a piece of DNA covalently bonded to a (cancer-causing) chemical.
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Card 2

Front

What are the 2 main types of spontaneous damage?

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Alterations in structure, and Oxidative damage

Card 3

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What three subcategories of alterations in structure are there?

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Preview of the front of card 3

Card 4

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What are tautomeric shifts? To form what? Which can...

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Preview of the front of card 4

Card 5

Front

Amino --> ? , Keto --> ?

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