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

CONSEQUENCES OF DNA DAMAGE
• Can increase frequency of mutations
• Mutations: nucleotide substitutions, deletions and insertions

CLINICAL CORRELATIONS

Skin melanomas

• Pyrimidine dimers produce helical distortions that result in skin cancers

Cigarette smoking

• Carcinogens in smoke form covalent bonds with DNA
• Disrupts H-bonding between nucleotides: causes frameshift
• Frameshift changes subsequent codons in DNA strand
• Constant exposure to carcinogens –> lung cancer

REPAIR MECHANISMS
• Mismatch-repair: fixes replication errors missed by DNA Polproofreading (cannot repair damage)
• Base excision repair: deamination, depurination and alkylation
• Nucleotide excision repair: pyrimidine dimers and bulky group addition