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