LECTURE 13&14-DNA damage and repair oops, ouch!

LECTURE 13&14-DNA damage and repair oops, ouch! -...

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Unformatted text preview: DNA damage and repair summary 1. Defects in repair cause disease 2. Common types of DNA damage 3. DNA repair pathways Direct enzymatic repair Base excision repair Nucleotide excision repair Mismatch repair Double-strand break repair Non-homologous end joining Homologous recombination DNA repair defects cause disease Common types of DNA damage -- 1 1. Depurination: A, G 2. Deamination: C --> U, A --> Hypoxanthine Common types of DNA damage -- 2 Pyrimidine dimers (UV induced). Repair pathways Common types of DNA damage -- 3 Two carcinogens that mutate (the P53 gene) by base alkylation + Mismatches (mistakes in DNA synthesis) I nterstrand cross-links, Double-strand DNA breaks 4 6 Diverse DNA repair systems • Augment DNA polymerase proofreading • Mostly characterized in bacteria • General mechanisms shared in eukaryotes 1. Direct repair, e.g. pyrimidine dimers 2. Base excision repair 3. Nucleotide excision repair 4. Mismatch excision repair 5. Double-strand break repair and recombination Base excision repair Base excision repair pathway (BER). (a) A DNA glycosylase recognizes a damaged base and cleaves between the base and deoxyribose in the backbone. (b) An AP endonuclease cleaves the phosphodiester backbone near the AP site. (c) DNA polymerase I initiates repair synthesis from the free 3’ OH at the nick, removing a portion of the damaged strand (with its 5’ → 3’ exonuclease activity) and replacing it with undamaged DNA. (d) The nick remaining after DNA polymerase I has dissociated is sealed by DNA ligase. AP= apurinic or apyrimidinic (a=without) Damaged base A DNA glycosylase initiates base excision repair Examples of bases cleaved by DNA glycosylases: Uracil (deamination of C) 8-oxoG paired with C (oxidation of G) Adenine across from 8-oxoG (misincorporation) Thymine across from G (5-meC deamination) Alkyl-adenine (3-meA, 7-meG, hypoxanthine) Damaged base Human alkyl-adenine DNA glycosylase DNA bent & modified base flipped out of duplex -- “Non-Watson-Crick” structure Diverse DNA repair systems...
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LECTURE 13&14-DNA damage and repair oops, ouch! -...

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