Types of DNA damage

Spontaneous Hydrolytic Damage - Going, Going, Guanine!

• Water attacks and breaks covalent bonds in DNA. Two main types:
  • Deamination: Loss of an amino group ($NH_2$) from a base.
    • Cytosine → Uracil (repaired by Base Excision Repair)
    • Adenine → Hypoxanthine
    • Guanine → Xanthine
    • 5-methylcytosine → Thymine (creates T-G mismatch)
  • Depurination: N-glycosidic bond between a purine base (A or G) and the sugar is cleaved.
    • Creates an AP (apurinic) site (abasic site).
    • Repaired by AP endonucleases in the BER pathway.

⭐ Deamination of cytosine to uracil is easily recognized as U is not in DNA. However, deamination of 5-methylcytosine (found in CpG islands) yields thymine, creating a T-G mismatch that is less efficiently repaired, leading to C→T point mutations.

Oxidative & Alkylating Agents - Chemical Chaos

• Oxidative Damage

  • Source: Reactive oxygen species (ROS) like $O_2^-$, $H_2O_2$, and $OH^•$ from normal metabolism, inflammation, and radiation.
  • Lesion: Guanine is oxidized to 8-oxoguanine.
  • Consequence: 8-oxoguanine mispairs with Adenine, causing a G:C → T:A transversion mutation.
  • Repair: Base Excision Repair (BER).

• Alkylating Damage

  • Source: Environmental chemicals (e.g., nitrosamines in smoked foods) and chemotherapy drugs.
  • Lesion: Addition of alkyl groups (e.g., methyl) to guanine (O6, N7) or adenine (N3).
  • Consequence: Causes mispairing (e.g., O6-methylguanine with Thymine) or creates bulky adducts that block replication.
  • Repair: BER, NER, or direct reversal by MGMT.

⭐ 8-oxoguanine-induced G:C → T:A transversions are among the most frequent somatic mutations found in human cancers, directly linking oxidative stress to carcinogenesis.

Radiation Damage - Dimer Disasters & Double Trouble

• UV Light (Non-ionizing):

  • Forms pyrimidine dimers (especially thymine dimers) via cyclobutane ring formation.
  • Creates a "kink" in the DNA helix, stalling replication & transcription.
  • Repaired by Nucleotide Excision Repair (NER).

• Ionizing Radiation (X-rays, γ-rays):

  • Generates reactive oxygen species (ROS) causing base/sugar damage.
  • Causes double-strand breaks (DSBs), the most lethal DNA lesion.
  • Repaired by Non-Homologous End Joining (NHEJ) or the higher-fidelity Homologous Recombination (HR).

⭐ High-Yield: Double-strand breaks are the primary mechanism by which radiotherapy kills cancer cells. A single unrepaired DSB can be sufficient to trigger apoptosis or lead to catastrophic chromosomal aberrations.

High‑Yield Points - ⚡ Biggest Takeaways

• Spontaneous damage includes depurination (loss of a purine base) and deamination (e.g., cytosine converting to uracil).
• Oxidative damage from reactive oxygen species (ROS) creates 8-oxoguanine, causing G:C → T:A transversions.
• UV radiation is the primary cause of pyrimidine (thymine) dimers, which kink the DNA helix.
• Ionizing radiation (X-rays, γ-rays) causes the most severe lesion: double-strand breaks.
• Chemical mutagens include alkylating agents and large bulky adducts (e.g., benzopyrene in tobacco smoke).