DNA Repair Lehninger chapters 8 and 25 Blackburn

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 (100 x a day) A G (Hyp) occurs 100 x slower 2. Hydrolysis of bond between sugar and base (apurinic residue) Occurs once every 105 purines in a day (10, 000 x 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 H 2 O 2, • OH, • O 2 -

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 Mut. L-Mut. S 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 Mut. L homolog, human Mut. S homolog Recombinational repair Recombination - linear sequence of DNA altered by cleavage and rejoining of chromosome (involves Rec. A protein) Repair of this type sometimes needed to reconstruct replication fork Human breast cancer genes (BRCA 1 and BRCA 2) produce proteins that interact with the human homolog of Rec. A, therefore these are linked to recombination repair 10% of breast cancers have defects in BRCA 1 or BRCA 2 Women with defects in these genes have a >80% chance of developing breast cancer