Lecture 3a - Methylpurine DNA glycosylase(MPG repair of...

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M ethylp urine DNA g lycosylase (MPG): repair of alkylated bases 7-meG quantitatively the major adduct following Sn1 and Sn2 methylating agents but 3-meA is thought to be the major cytotoxic adduct MPG is only glycosylase that recognizes alkylating lesions in mammals -MPG does not seem to release products generated by chloroethylating agents
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AP endonucleases and downstream BER proteins after AP site generated, BER pathway usually proceeds using common set of proteins: AP endonuclease makes a nick 5’ to the AP site, leaving 3’ hydroxyl and 5’ phosphate termini the presence of these 5’ and 3’ groups permits a DNA polymerase to fill the gap a DNA ligase seals the nick In addition to AP endonuclease activity , these enzymes possess phosphodiesterase activity for removal of fragmented sugar residues, such as phosphoglycolate from 3’ terminus of strand breaks induced by oxidants this activity can remove 3’ terminal groups left by AP lyases following at AP sites
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Damage initially processed by glycosylases with 3’ AP lyase activity generally is repaired by the short patch BER pathway Damage initially processed by simple glycosylases use 5’ APE and long patch BER
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hOGG1 catalytic site
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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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Photolyases-what we don’t have direct mode of repair bind to DNA damage induced by UV light in a light-independent fashion the repair process is driven by exposure to light revert both cyclobutane pyrimidine dimers (CPD) and (6-4) photoproducts -NOT in placental mammals but in marsupials and everything else
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Photolyases
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Nucleotide Excision Repair- Overview bulky adducts helix distortion sensing mechanism originally due to UV light three diseases
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NER-what does it fix? repairs adducts of chemicals covalently bond to DNA the structure of the agent and the means through which it binds to DNA are diverse e.g. acetylaminofluorene-guanine cisplatin-guanine psoralen-thymine thymine dimers 6-4 photoproducts common feature:lesions that cause major helical distortion, and the chemical-DNA adduct is ‘bulky’
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