1. DNA Damage Caused by Radiation
Radiation exposure leads to a variety of DNA lesions. These include:
- Single Strand Breaks (SSBs) - Breaks in one of the DNA strands.
- Double Strand Breaks (DSBs) - Breaks in both strands of the DNA helix.
- Base Damage - Modifications to the nitrogenous bases of DNA.
- Protein–DNA Cross-links - Covalent bonding between proteins and DNA.
- Protein–Protein Cross-links - Bonds formed between two proteins within the cell.
The frequency of these lesions is quite high after radiation exposure. For example, with a dose of 1–2 Gy, a cell may incur:
- Base damages: >1000
- Single strand breaks (SSBs): ~1000
- Double strand breaks (DSBs): ~40
Double strand breaks (DSBs) are especially critical, as they are strongly linked to cell death, carcinogenesis, and hereditary effects. The number of DSBs correlates with radiosensitivity and survival at lower doses, and unrepaired or misrepaired DSBs can have severe consequences at higher doses.
2. DNA Repair Mechanisms
DNA repair mechanisms are vital for cells to recover from radiation and other damaging agents. Several repair pathways exist, and their effectiveness depends on the type of DNA damage:
2.1. Repair of Base Damage, SSBs, and DSBs
There are three primary types of repair for minor DNA lesions:
- Base Excision Repair (BER) - Repairs base modifications such as oxidation and alkylation.
- Mismatch Repair (MMR) - Corrects mispaired bases during DNA replication.
- Nucleotide Excision Repair (NER) - Fixes large DNA adducts and intercalation damage.
These repair mechanisms involve cutting out the damaged segment and filling the gap with the correct sequence using the undamaged strand as a template. However, DSBs require more complex repair processes.
2.2. Repair of Double Strand Breaks (DSBs)
DSBs are more complicated to repair and involve two main pathways:
- Non-Homologous End Joining (NHEJ) - This pathway operates on blunt-ended DNA breaks. It involves the recognition of broken DNA ends, cleaning them up, and ligating the ends together. NHEJ is active throughout the cell cycle and is error-prone because it does not rely on a template.
- Homologous Recombination (HR) - This repair process uses the undamaged homologous chromosome or sister chromatid as a template to repair the break. HR is accurate and occurs mainly in the S/G2 phase of the cell cycle, when homologous sequences are available.
While HR is error-free, NHEJ can lead to mutations, deletions, or chromosomal translocations due to the lack of sequence homology.
3. Consequences of DNA Damage
Unrepaired or misrepaired DNA damage can have significant biological consequences:
- Mutations - Lead to changes in the DNA sequence that can result in cancer or other genetic diseases.
- Chromosomal Aberrations - DSBs that are not properly repaired can lead to chromosomal translocations, deletions, or other structural abnormalities, which are often lethal or carcinogenic.
- Cell Death - If the damage is too severe, the cell may undergo apoptosis (programmed cell death) or necrosis.
DSBs, especially those that are misrepaired, are considered a major factor in the induction of cancers, genetic defects, and cell death after radiation exposure.
Key Takeaway
Radiation-induced DNA damage, particularly double strand breaks, plays a critical role in the biological effects of radiation. The ability of cells to repair DNA damage through mechanisms such as NHEJ and homologous recombination influences their survival and risk of developing mutations or cancer. Efficient DNA repair is essential for cellular recovery after radiation exposure.