(1) DNA Repair

Overview of DNA Repair

  • DNA repair involves processes that allow cells to identify and correct damage to DNA.

  • Essential for maintaining genomic integrity.

Sources of DNA Damage

Endogenous Sources

  • Internal damage originating from normal metabolic activities within the cell.

Exogenous Sources

  • External damage due to environmental factors (e.g., UV light, chemicals).

Incidence of Damage

  • Human cells can experience up to 1 million instances of DNA damage per cell, per day.

  • DNA repair processes are continuously active in response to this damage.

Recognition of DNA Damage

  • Damage alters the spatial configuration of the DNA helix, leading to detectable changes (e.g., bulges).

  • Specific repair molecules bind at or near the site of damage to initiate repair processes.

Types of DNA Repair Mechanisms

Single-Strand Repair Mechanisms

  • Nucleotide Excision Repair (NER)

    • Repairs damage caused by UV light leading to covalent linkages known as pyrimidine dimers (thymine or cytosine).

    • Enzymes called endonucleases remove damaged nucleotides; DNA polymerase replaces them; DNA ligase seals the gap.

    • Example: Failure in NER can lead to melanoma.

  • Base Excision Repair (BER)

    • Addresses specific base damage, such as deamination caused by certain chemicals (e.g., nitrates).

    • Involves glycosylases to remove damaged bases, followed by cutting the phosphodiester backbone and filling in the gap.

  • Mismatch Repair (MMR)

    • Corrects errors from DNA replication or recombination that result in mis-paired nucleotides.

    • In bacteria, methylation distinguishes the new strand; eukaryotic mechanisms are less well understood.

Double-Strand Repair Mechanisms

  • Damage involving both strands can occur from ionizing radiation (e.g., gamma rays, x-rays).

  • Non-Homologous End Joining (NHEJ)

    • Involves a specialized ligase that directly connects the ends of broken DNA strands without requiring a template.

  • Microhomology-Mediated End Joining (MMEJ)

    • Aligns strands using a short complementary sequence, removes mismatched bases, fills in gaps.

  • Homologous Recombination (HR)

    • Requires similar sequences to act as templates for repair, typically using a sister chromatid.

    • Involves enzymatic machinery similar to that used during meiosis crossover.

Factors Influencing Repair Rate

  • The efficiency and speed of DNA repair can vary based on:

    • Cell type.

    • Age of the cell.

    • Extracellular environment (e.g., presence of nutrients, damage levels).

Possible Outcomes of Excessive DNA Damage

  1. Senescence

    • Irreversible dormancy where the cell stops dividing but remains metabolically active (similar to hibernation).

  2. Apoptosis

    • Programmed cell death occurs when damage is beyond repair.

  3. Unregulated Cell Division

    • Can lead to tumor formation and cancerous growth if repair mechanisms fail and damage accumulates.