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DNA Repair Lehninger, chapters 8 and 25 Blackburn & Gait, Ch. 6 and 8

DNA Repair Lehninger, chapters 8 and 25 Blackburn & Gait, Ch. 6 and 8 Know main types of DNA damage Know repair mechanisms used for each type of damage Know the difference between transition and transversion Understand why defects in repair mechanisms could lead to cancers. DNA metabolism.

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DNA Repair Lehninger, chapters 8 and 25 Blackburn & Gait, Ch. 6 and 8

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  1. DNA Repair Lehninger, chapters 8 and 25 Blackburn & Gait, Ch. 6 and 8 Know main types of DNA damage Know repair mechanisms used for each type of damage Know the difference between transition and transversion Understand why defects in repair mechanisms could lead to cancers

  2. DNA metabolism DNA Repair DNA damage from: 1. spontaneous loss of exocyclic amino group (deamination) C  U occurs once every 107 C residues in a day (100x a day) A  G (Hyp) occurs 100x slower 2. Hydrolysis of bond between sugar and base (apurinic residue) Occurs once every 105 purines in a day (10,000x a day) Slower for pyrimidines

  3. DNA metabolism DNA Repair DNA damage from: 3. UV damage causes pyrimidine dimers

  4. DNA metabolism DNA Repair DNA damage from: 4. Reactive chemicals Nitrous acid precursors Alkylating agents (nitrogen mustard, DMS, SAM)

  5. DNA metabolism DNA Repair DNA damage from: 5. Oxidative Damage H2O2, •OH, •O2-

  6. DNA metabolism DNA Damage & Repair

  7. DNA metabolism DNA Repair

  8. DNA metabolism DNA Repair In bacteria

  9. DNA metabolism DNA Repair

  10. DNA metabolism DNA Mismatch Repair Correction of mismatches increases fidelity by 100 to 1000-fold Repairs mismatches up to 1000 bp from hemi-methylated GATC

  11. DNA metabolism DNA Mismatch Repair Binds all mismatches except C-C Binds to MutL-MutS and methylated GATC

  12. DNA metabolism DNA Mismatch Repair

  13. DNA metabolism DNA Base-excision Repair DNA glycosylases recognize deaminations and remove them leaving an apurinic/apyrimidinic site (AP site)

  14. DNA metabolism DNA Nucleotide-excision Repair Used to repair DNA lesions that cause large distortions in DNA helix (pyr dimers)

  15. DNA metabolism Photolyase

  16. DNA damage - mutation

  17. DNA damage - mutation

  18. DNA metabolism DNA SOS Repair Responds to extensive DNA damage, coordinated induction of a variety of genes

  19. DNA metabolism DNA Repair Defects in genes encoding proteins involved in mismatch repair, nucleotide-excision repair, and recombinational repair can cause cancer Nucleotide-excision repair sole repair pathway for pyrimidine dimers genetic defect causes XP, xeroderma pigmentosa, these individuals are extremely sensitive to sunlight and quickly develop sunlight-induced skin cancer Mismatch repair Hereditary nonpolyposis colon cancer (HNPCC) linked to defects in these genes Defects in human MutL homolog, human MutS homolog Recombinational repair Recombination - linear sequence of DNA altered by cleavage and rejoining of chromosome (involves RecA protein) Repair of this type sometimes needed to reconstruct replication fork Human breast cancer genes (BRCA1 and BRCA2) produce proteins that interact with the human homolog of RecA, therefore these are linked to recombination repair 10% of breast cancers have defects in BRCA1 or BRCA2 Women with defects in these genes have a >80% chance of developing breast cancer

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