Radiation zaps DNA, causing chaos in our chromosomes. It's like a molecular wrecking ball, smashing genes and scrambling our genetic code. This damage can lead to all sorts of problems, from cell death to cancer.
But our cells aren't helpless. They've got repair mechanisms to fix the damage. Sometimes these repairs work perfectly, but other times they mess up, creating even more chromosomal mayhem. It's a constant battle between radiation and our cellular repair crews.
Radiation-Induced Chromosomal Damage
Direct and Indirect DNA Damage Mechanisms
- Ionizing radiation directly interacts with DNA molecules causing ionization and excitation of atoms within the DNA structure
- Free radicals primarily hydroxyl radicals produced through radiolysis of water molecules in cells indirectly damage DNA
- Radiation-induced DNA damage includes single-strand breaks, double-strand breaks, base modifications, and DNA-protein crosslinks
- Linear energy transfer (LET) of radiation influences spatial distribution and complexity of DNA damage
- Clustered DNA damage consisting of multiple lesions within 1-2 helical turns characterizes radiation-induced chromosomal damage
- Example: Multiple oxidized bases and strand breaks within a small DNA region
Immediate and Delayed Effects
- Radiation causes immediate damage to DNA structure
- Delayed effects occur through genomic instability and bystander effects
- Genomic instability leads to increased mutation rates in subsequent cell generations
- Bystander effects induce damage in neighboring non-irradiated cells
- Persistent chromosomal damage can result in:
- Cell cycle arrest
- Apoptosis
- Carcinogenesis
DNA Double-Strand Breaks in Aberrations
DSB Formation and Consequences
- DNA double-strand breaks (DSBs) form most critical lesions for chromosomal aberrations
- Frequency of radiation-induced chromosomal aberrations directly proportional to number of unrepaired or misrepaired DSBs
- DSBs lead to various types of chromosomal aberrations:
- Deletions (loss of genetic material)
- Inversions (reversal of DNA segment)
- Translocations (exchange of genetic material between chromosomes)
- Dicentric chromosomes (two centromeres on one chromosome)
- Spatial proximity of DSBs within nucleus influences likelihood of aberration formation through illegitimate rejoining
- Example: DSBs in close proximity more likely to form translocations
Complexity and Persistence of DSBs
- Complexity of DSBs particularly those induced by high-LET radiation affects probability of misrepair and aberration formation
- High-LET radiation (alpha particles) produces more complex DSBs than low-LET radiation (X-rays)
- Persistent DSBs can result in:
- Chromosome fragmentation
- Chromosome loss leading to aneuploidy
- Cell death through mitotic catastrophe
- DSB complexity influences repair pathway choice and efficiency
- Simple DSBs more easily repaired by Non-Homologous End Joining (NHEJ)
- Complex DSBs may require Homologous Recombination (HR) for accurate repair
Cellular Repair of Chromosomal Aberrations
DNA Repair Pathways
- Non-homologous end joining (NHEJ) and homologous recombination (HR) serve as primary DNA repair pathways for double-strand breaks
- NHEJ remains active throughout cell cycle and can lead to small insertions or deletions at repair site potentially causing mutations
- Example: NHEJ may insert or delete a few nucleotides at the break site
- HR operates most actively during S and G2 phases and requires homologous template for accurate repair reducing likelihood of aberrations
- Example: HR uses sister chromatid as a template for precise repair
- Misrepair through NHEJ can result in chromosomal translocations when DSBs from different chromosomes incorrectly join
- Example: Philadelphia chromosome in chronic myeloid leukemia
Factors Influencing Repair Pathway Choice
- Choice between NHEJ and HR influenced by factors such as:
- Cell cycle phase (NHEJ predominant in G1, HR in S/G2)
- Chromatin structure (open chromatin favors HR)
- Complexity of DSB (simple breaks favor NHEJ, complex breaks favor HR)
- Alternative end joining pathways such as microhomology-mediated end joining (MMEJ) contribute to formation of chromosomal aberrations
- MMEJ uses short homologous sequences to align broken ends, often resulting in deletions
- Kinetics of DSB repair influence probability of aberration formation with slower repair increasing likelihood of misrejoining
- Rapid repair reduces chance of illegitimate rejoining between distant DSBs
Factors Influencing Chromosomal Aberrations
Radiation Characteristics and Dose
- Radiation dose and dose rate significantly affect frequency and complexity of chromosomal aberrations
- Higher doses produce more aberrations
- Lower dose rates allow more time for repair, potentially reducing aberration frequency
- Quality of radiation (LET) influences spatial distribution of energy deposition and resulting pattern of DNA damage
- High-LET radiation (neutrons) produces more complex aberrations than low-LET radiation (gamma rays)
- Cell cycle phase at time of irradiation impacts types of aberrations observed with G1 phase cells more prone to chromosome-type aberrations
- Example: Dicentrics more common in G1 irradiated cells
Biological and Environmental Factors
- Inherent radiosensitivity of different cell types and tissues affects frequency of chromosomal aberrations
- Lymphocytes more radiosensitive than fibroblasts
- Genetic factors including mutations in DNA repair genes modulate individual's susceptibility to radiation-induced chromosomal damage
- Example: Ataxia telangiectasia patients show increased chromosomal aberrations after radiation exposure
- Environmental factors such as oxygen concentration and temperature influence formation and persistence of chromosomal aberrations
- Higher oxygen levels increase aberration frequency due to enhanced free radical production
- Time between irradiation and observation affects observed frequency of aberrations due to cell division and selection processes
- Unstable aberrations (dicentrics) decrease in frequency over time as cells divide