Radiation-Induced DNA Damage

Radiation Interaction with Cells - Target Hit!

• Cellular damage mechanisms:
  • Direct Action: Radiation directly ionizes critical cellular target (DNA). Predominant for high-LET radiation (α-particles, neutrons).
  • Indirect Action: Radiation ionizes water (main cell constituent), creating free radicals that diffuse to damage DNA.
    • Primary mechanism for low-LET radiation (X-rays, γ-rays).
    • Key radical: $\cdot OH$ (hydroxyl) - most damaging.
    • Water radiolysis yields: $\cdot OH, H\cdot, e_{aq}^-$.

⭐ For X & γ-rays, ~2/3 DNA damage is indirect, mainly via $\cdot OH$ radicals.

Types of DNA Lesions - Molecular Scars

• Single-Strand Breaks (SSBs):
  • Frequent, efficiently repaired (e.g., by BER).
  • Lower biological significance than DSBs.
  • Common from indirect action of low-LET radiation.
• Double-Strand Breaks (DSBs):
  • Most lethal; primary cause of cell killing, chromosomal aberrations, mutations.
  • Repair is complex (NHEJ, HRR).
  • Caused by direct action or clustered damage (high-LET).
• Base Damage:
  • Oxidation (e.g., 8-oxoguanine), alkylation.
  • Repaired by BER; mutagenic if misrepaired.
• Crosslinks:
  • DNA-Protein Crosslinks (DPCs).
  • Intra-strand & Inter-strand crosslinks (ICLs).
  • Block replication & transcription.

⭐ Double-Strand Breaks (DSBs) are the most critical lesions for radiation-induced cell death and genomic instability. Misrepair leads to mutations and chromosomal aberrations.

DNA Repair Pathways - Cellular ER

• Cells use diverse pathways to mend DNA damage, vital for survival.
• Base Excision Repair (BER):
  • Repairs single base damage (oxidation, alkylation).
  • Key enzymes: Glycosylases, AP endonuclease, DNA Pol β, Ligase.
  • High fidelity.
• Nucleotide Excision Repair (NER):
  • Removes bulky adducts (e.g., UV-induced pyrimidine dimers).
  • Excises damaged DNA segment.
  • High fidelity.
• Double-Strand Break (DSB) Repair:
  • Homologous Recombination (HR):
    • Error-free; uses sister chromatid as template.
    • Predominant in S/G2 phase.
    • Key proteins: BRCA1/2, RAD51.
  • Non-Homologous End Joining (NHEJ):
    • Error-prone; directly ligates broken ends.
    • Active throughout cell cycle (esp. G0/G1).
    • Key proteins: Ku70/80, DNA-PKcs.
    • 📌 Mnemonic: "No Homie? Just Join!"

⭐ NHEJ is the predominant pathway for repairing DNA double-strand breaks in mammalian cells, especially outside of S/G2 phase.

Cellular Fates & Modifiers - Damage Outcomes

• Cellular Fates (Post-Irradiation):

  • Cell Cycle Arrest: Checkpoints (G1/S, G2/M) for DNA repair.
  • Apoptosis: Programmed cell death (e.g., via p53).
  • Senescence: Irreversible growth arrest.
  • Mitotic Catastrophe: Cell death due to aberrant mitosis.
  • Genomic Instability: ↑Mutations, chromosomal aberrations → carcinogenesis.

• Modifiers of Radiation Effect:

  • LET (Linear Energy Transfer): ↑LET → ↑RBE (Relative Biological Effectiveness).
  • Dose: ↑Dose → ↑Effect.
  • Dose Rate: ↓Dose rate → ↓Effect (more time for repair).
  • Oxygen Effect: O₂ "fixes" free radical damage, making it permanent.
    • OER (Oxygen Enhancement Ratio) = $D_{hypoxia} / D_{aerated}$ for same biological effect.
    • Value: ~2.5-3.5 for X-rays/γ-rays (low-LET).
    • ↓OER with ↑LET (approaches 1 for high-LET like α-particles).

⭐ Oxygen is the most potent chemical radiosensitizer; the OER is maximal for low-LET radiation and significantly reduced for high-LET radiation.

High‑Yield Points - ⚡ Biggest Takeaways

• Indirect action (via •OH radicals) is primary for X-rays/gamma rays.
• Direct action dominates for high-LET radiation (alpha, neutrons).
• DSBs are most biologically significant/lethal DNA lesions.
• SSBs are the most frequent DNA damage.
• Repair: BER for SSBs; NHEJ & HR for DSBs.
• Most radiosensitive: M & G2 phases; most radioresistant: late S phase.
• Oxygen enhances damage (OER ~2.5-3.5 for low-LET).