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DNA Damage & Repair
DNA DAMAGE MECHANISMS
Endogenous Agents
Spontaneous chemical reactions
1. Deamination: nucleotides lose amine groups
• Cytosine --> uracil
• Adenine --> hypoxanthine
2. Depurination: purine (adenine or guanine) released from DNA
• Bond between deoxyribose and purine base spontaneously cleaves
• Produces AP site (apurinic site)
Exogenous Agents
Exposure to mutagens (chemicals or radiation)
1. Pyrimidine dimers: induced by UV light exposure
• Cyclobutane ring forms between adjacent pyrimidines (often thymines)
• Distorts the DNA double helix
2. Alkylation: addition of methyl/ethyl groups to nucleotides
• -CH3 or –CH2CH3 add to nitrogenous bases at numerous positions
3. Bulky group addition: exposure to carcinogens
• i.e. benzo(a)pyrene: aromatic, polycyclic structure can react with purines/pyrimidines at numerous positions
• Cause distortions in DNA helix
- Carcinogen: Cancer-causing mutagen
REPAIR MECHANISMS
• Mismatch-repair: fixes replication errors missed by DNA Pol proofreading (cannot repair damage)
• Base excision repair: deamination, depurination and alkylation
• Nucleotide excision repair: pyrimidine dimers and bulky group addition
CONSEQUENCES OF DNA DAMAGE
• Can increase frequency of mutations
• Mutations: nucleotide substitutions, deletions and insertions