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rincrocci
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Spontaneous Mutations
- Depurination most common type of naturally occurring chem. Change
- Thru reaction with WATER, can remove A or G from DNA, leaving sugar-phosphate backbone intact.
- Generally recognized by DNA repair enzymes, to assist in 10,000 purines lost every 20hrs at 37degrees per cell.
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Base loss through depurination
- During replication: if not repaired, newly synthesized strand will INSERT a random nucleotide (as there is no template for complementary base at apurinic site), usually A
- As the next round of replication starts, the newly synthesized strand will now have A, which will then be complementary replicated w/T, which will lead to permanent mutation.
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Role of mutations in aging germ cells and brain cells
- PATERNAL Age Effect:
- Spermatogenesis is a CONTINUOUS process from puberty til death
- Inefficiency of DNA repair pathways
- In mouse exp. The cells with higher the rate of replication and division showed INCREASE mutagenesis.
- Also showed that as more DNA damage occurred (with older mice) there was LESS DNA amplification
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Mutations in Intestines related to aging:
- With duodenum: mutation FREQUENCY Increased w/age
- With Duodenum and jejunum: MORE mutation in MUCOSAL vs. serosal layers (ileum showed no change b/w the 2)
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External Mutations
- Common UV radiation mechanism
- Mostly involves UVB photons being ABSORBED by DNA bases (mostly pyrimidines)
- Thymine cyclobutane dimer forms
- 2 or more unsaturated molecules combine to form CYCLIC adduct, causing reduction in bond multiplying.
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Effects of UV radiation on DNA
- UVB being absorbed causes thymine dimers to form, causing SUNBURN and production of MELANIN
- INDIRECT DNA damage occurs through chromophore forming Free Radicals (NON-Sunburn..so NO warning sign or pain)
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Formation of free radicals
- UV light can be absorbed by CHROMOPHORE
- Chromophore is now EXCITED
- Reactions occur b/w this chromophore and DNA to Produce FREE Radicals
- Free radicals can be the addition of an OH group through OXIDATION, or add’n of OXYGEN singlet (O2)
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Enzymes that STOP free radicals
- Superoxide dismutase: converts Superoxide back into diatomic oxygen
- Catalayse: converts H2O2 to>> O2 and H20
- Glutothione peroxidase: H202 to >> O2
- Vitamin C & E and melatonin: good defense for FREE radicals, but NO Enzyme against it, it’s too fast and small
- Lycopene is good to take (tomato paste) as well
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Polycyclic Aromatic Hydrocarbons (PAHs):
- Carcinogenic and form from incomplete combustion organic materials
- Can BIND to DNA
- Most potent is BENZO(a)PYRENE
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Binding of PAHs with DNA
- Large aromatic bound structures IMPEDE DNA replication and disturb normal FXN
- Add’n of BP distorts angle of DNA, causing a LOSS of hydrogen bonds
- 2 BP conformations possible: Cys and Trans
- Cis: Intercalated and MORE energenetically STABLE, therefore more detrimental to replication (frameshifts, loss of H+, structure changes)
- Trans: Binds to MINOR groove of DNA, where it ALLOWS for DNA replication to occur
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p53:
- Tumor SUPPRESSING protein: prevents cells from DIVIDING inappropriately
- Deficiency in this can lead to tumor growth
- 50% of cancers known to have mutations in p53
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