Download DNA damage/repair

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
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
DNA metabolism
DNA Repair
DNA damage from:
3. UV damage causes pyrimidine dimers
DNA metabolism
DNA Repair
DNA damage from:
4. Reactive chemicals
Nitrous acid precursors
Alkylating agents (nitrogen
mustard, DMS, SAM)
DNA metabolism
DNA Repair
DNA damage from:
5. Oxidative Damage
H2O2, •OH, •O2-
DNA metabolism
DNA Damage & Repair
DNA metabolism
DNA Repair
DNA metabolism
DNA Repair
In bacteria
DNA metabolism
DNA Repair
DNA metabolism
DNA Mismatch Repair
Correction of mismatches increases fidelity by 100 to 1000-fold
Repairs mismatches up to
1000 bp from hemimethylated GATC
DNA Mismatch Repair
DNA metabolism
Binds all mismatches
except C-C
Binds to MutL-MutS
and methylated GATC
DNA metabolism
DNA Mismatch
Repair
DNA metabolism
DNA Base-excision Repair
DNA glycosylases recognize deaminations and remove them leaving an
apurinic/apyrimidinic site (AP site)
DNA metabolism
DNA Nucleotide-excision Repair
Used to repair DNA lesions that cause large distortions in DNA
helix (pyr dimers)
DNA metabolism
Photolyase
DNA damage - mutation
DNA damage - mutation
DNA metabolism
DNA SOS Repair
Responds to extensive DNA
damage, coordinated induction of a
variety of genes
DNA Repair
DNA metabolism
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