Double-strand break repair

DSB Repair - The DNA ER

• Homologous Recombination (HR): High-fidelity, "error-free" repair.

  • Uses sister chromatid template during S and G2 phases.
  • Mutations in BRCA1/2 genes impair HR, increasing risk for breast and ovarian cancer.

• Non-Homologous End Joining (NHEJ): Predominant but error-prone mechanism.

  • Directly ligates broken ends; active in G0/G1 phases.
  • May introduce insertions or deletions (indels).

⭐ Ataxia-telangiectasia is caused by a defect in the ATM gene, a key sensor of double-strand breaks, leading to failed repair and neurological/immunological symptoms.

Homologous Recombination - The Perfectionist

• Mechanism: High-fidelity, error-free repair for DNA double-strand breaks (DSBs).
• Template: Requires an undamaged homologous chromosome or sister chromatid.
  • Primarily active during the S & G2 phases of the cell cycle.
• Key Proteins: Involves BRCA1, BRCA2, & RAD51.
  • Mutations are linked to Fanconi anemia and cancers (breast, ovarian, prostate).

⭐ Synthetic Lethality: Cancers with BRCA1/2 mutations are highly sensitive to PARP inhibitors. With faulty HR, the cell relies on PARP for single-strand break repair; inhibiting it causes catastrophic DNA damage and cell death.

NHEJ - The Quick & Dirty Fix

• Dominant pathway for repairing double-strand breaks (DSBs) in the G0/G1 phase.
• Mechanism: Direct ligation of broken DNA ends without a homologous template.

• Outcome: Fast but error-prone, often resulting in small insertions or deletions (indels).

⭐ The NHEJ machinery is essential for V(D)J recombination, the process that generates diversity in antibodies and T-cell receptors.

Clinical Tie-ins - When Repair Fails

• Ataxia-Telangiectasia (AR)
  • Defect in ATM gene, a key sensor for DSBs, impairing NHEJ.
  • Presents with cerebellar ataxia, oculocutaneous telangiectasias, and severe immunodeficiency (↓ IgA).
  • Marked sensitivity to ionizing radiation.
• BRCA1 & BRCA2 Gene Mutations
  • Impair Homologous Recombination (HR).
  • Confers high risk for breast, ovarian, prostate, and pancreatic cancers.
• Fanconi Anemia (AR)
  • Caused by mutations in genes essential for HR.
  • Leads to bone marrow failure, developmental anomalies, and predisposition to AML.

⭐ PARP inhibitors (e.g., Olaparib) are synthetically lethal in BRCA-mutated cancers, as they block single-strand break repair, leaving the cell with no effective DNA repair mechanism.

High‑Yield Points - ⚡ Biggest Takeaways

• Homologous Recombination (HR) is the high-fidelity, template-dependent pathway, primarily active in S/G2 phases.
• Non-Homologous End Joining (NHEJ) is error-prone, does not require a template, and is active in all phases, especially G1.
• BRCA1 & BRCA2 mutations impair HR and are strongly associated with breast, ovarian, and pancreatic cancers.
• Ataxia-telangiectasia is caused by a mutation in the ATM gene, a crucial sensor for double-strand breaks.
• NHEJ is also essential for V(D)J recombination in lymphocytes.