dna repair lehninger, chapters 8 and 25 blackburn & gait, ch. 6 and 8 know main types of dna...
TRANSCRIPT
DNA Repair
Lehninger, chapters 8 and 25Blackburn & Gait, Ch. 6 and 8
Know main types of DNA damageKnow repair mechanisms used for each type of damageKnow the difference between transition and transversionUnderstand why defects in repair mechanisms could lead to cancers
DNA metabolism
DNA RepairDNA 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 RepairDNA damage from:3. UV damage causes pyrimidine dimers
DNA metabolism
DNA RepairDNA damage from:4. Reactive chemicals
Nitrous acid precursorsAlkylating agents (nitrogen mustard, DMS, SAM)
DNA metabolism
DNA RepairDNA damage from:5. Oxidative Damage
H2O2, •OH, •O2-
DNA metabolismDNA Damage & Repair
DNA metabolism
DNA Repair
DNA metabolism
DNA RepairIn bacteria
DNA metabolism
DNA Repair
DNA Mismatch RepairCorrection of mismatches increases fidelity by 100 to 1000-fold
DNA metabolism
Repairs mismatches up to 1000 bp from hemi-methylated GATC
Binds all mismatches except C-C
Binds to MutL-MutS and methylated GATC
DNA Mismatch RepairDNA metabolism
DNA metabolism
DNA Mismatch Repair
DNA Base-excision Repair
DNA glycosylases recognize deaminations and remove them leaving an apurinic/apyrimidinic site (AP site)
DNA metabolism
DNA Nucleotide-excision RepairUsed to repair DNA lesions that cause large distortions in DNA helix (pyr dimers)
DNA metabolism
Photolyase
DNA metabolism
DNA damage - mutation
DNA damage - mutation
DNA SOS RepairResponds to extensive DNA damage, coordinated induction of a variety of genes
DNA metabolism
DNA Repair
Defects in genes encoding proteins involved in mismatch repair, nucleotide-excision repair, and recombinational repair can cause cancer
Nucleotide-excision repairsole 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 repairHereditary nonpolyposis colon cancer (HNPCC) linked to defects in these genes
Defects in human MutL homolog, human MutS homolog
Recombinational repairRecombination - 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 BRCA2Women with defects in these genes have a >80% chance of developing breast cancer
DNA metabolism