Lecture 3b - Lecture 3 Overview Photolyases Nucleotide...

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Lecture 3 Overview • Photolyases Nucleotide Excision Repair –overview -historical -what does it fix -how does it fix -global genome vs. transcription- coupled
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Nucleotide Excision Repair of DNA damage by chemical adducts ‘central tenet’ of chemical carcinogenesis is that covalent binding of carcinogens to DNA is causally is ‘causally related’ to tumorigenesis 1. majority of carcinogens are mutagens 2. mutagenic and carcinogenic properties of many carcinogens depends on their conversion to electrophilic derivatives that react with nucleophilic sites within DNA 3. extent of DNA adduct formation can often be correlated with the magnitude of mutagenic and carcinogenic responses 4. activation of certain proto-oncogenes can be accomplished through the interaction of carcinogens with DNA
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N -Nitrosamines exposure from foods, beverages, tobacco, cosmetics, rubber products, hydraulic fluids are chemically inert until metabolized to reactive electrophiles before binding to cellular macromolecules metabolism involves oxidation of carbon adjacent to amine nitrogen (alpha – hydroxylation) resultant alpha-hydroxy- N -nitrosoalkylamines are unstable: decompose to aldehydes and alkyl diazohydroxides: latter can alkylate DNA primary site of substitution is N 7 of guanine
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Polycyclic Aromatic Hydrocarbons (PAHs) byproducts of combustion processes – widespread exposure initial step in activation of PAHs is an epoxidation step in a benzene ring
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Polycyclic Aromatic Hydrocarbons (PAHs) typical adducts are at the N2 site of guanine or the N6 site of adenine
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Aromatic amines/amides exposure : various industrial processes, cigarette smoke and certain foods aromatic amines implicated in the induction of bladder cancer in humans initial activation be N-oxidation to give N-hydroxy arylamines and N-hydroxy arylamides, which both can react with DNA, the major adduct is with C 8 of guanine
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Aflatoxins exposure through consumption of mouldy cereals, grains, nuts four major naturally occurring forms: B 1 , B 2 , G 1 , and G 2 the B 1 form (AFB 1 ) is more abundant and most carcinogenic -metabolic activation to give AFB 1 -8,9-oxide which reacts with the N 7 of guanine -positive correlation exists between the amount of AFB 1 ingested and the incidence of liver cancer
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Discovery of Platinum anticancer drugs Cisplatin –chance discovery in 1965 by laboratory studying effect of electrical current on Escherichia coli electrical current itself did not inhibit cell division of
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