☢️Radiobiology Unit 8 – Radiation-Induced Genomic Mutations

Key Concepts and Terminology

• Ionizing radiation transfers energy to atoms or molecules, causing ionization and potential damage to biological systems
• Linear energy transfer (LET) measures the amount of energy deposited per unit length of the radiation track
  • Low LET radiation (X-rays, gamma rays) deposits energy sparsely, causing sparse ionization events
  • High LET radiation (alpha particles, neutrons) deposits energy densely, causing clustered ionization events
• Relative biological effectiveness (RBE) compares the biological damage caused by different types of radiation relative to a reference radiation (usually X-rays or gamma rays)
• Direct effects of radiation involve direct interaction of radiation with critical targets (DNA, proteins), leading to ionization and damage
• Indirect effects of radiation involve the production of reactive oxygen species (ROS) through radiolysis of water, which can subsequently damage critical targets
• Radiosensitivity refers to the susceptibility of cells, tissues, or organisms to the harmful effects of ionizing radiation
• Dose-response relationship describes the correlation between the absorbed dose of radiation and the biological effect observed

Types of Radiation and Their Effects

• Electromagnetic radiation includes X-rays and gamma rays, which have high penetrating power and low LET
  • X-rays are produced by the deceleration of electrons or electronic transitions in atoms
  • Gamma rays originate from the decay of radioactive nuclei or nuclear reactions
• Particulate radiation includes alpha particles, beta particles, and neutrons, which have varying penetrating power and LET
  • Alpha particles are helium nuclei with high LET and low penetrating power
  • Beta particles are electrons or positrons with intermediate LET and penetrating power
  • Neutrons are uncharged particles with high LET and penetrating power
• Cosmic radiation originates from space and consists of high-energy protons, alpha particles, and heavier nuclei
• Terrestrial radiation comes from naturally occurring radioactive materials in the Earth's crust (uranium, thorium, radon)
• Internal radiation exposure occurs when radioactive materials are ingested, inhaled, or absorbed into the body
• External radiation exposure occurs when the body is exposed to radiation from an external source

DNA Damage Mechanisms

• Direct DNA damage occurs when radiation directly interacts with DNA, causing ionization and breakage of chemical bonds
  • Single-strand breaks (SSBs) involve the breakage of one strand of the DNA double helix
  • Double-strand breaks (DSBs) involve the simultaneous breakage of both strands of the DNA double helix and are more difficult to repair accurately
• Indirect DNA damage occurs when radiation interacts with water molecules, producing reactive oxygen species (ROS) that can subsequently damage DNA
  • Hydroxyl radicals (•OH) are highly reactive and can cause oxidative damage to DNA bases and sugar-phosphate backbone
  • Superoxide anions (O2•-) and hydrogen peroxide (H2O2) can also contribute to oxidative stress and DNA damage
• DNA base modifications can occur due to oxidation, deamination, or alkylation of DNA bases, potentially leading to mutations if not repaired
• Bulky DNA adducts can form when DNA bases react with exogenous or endogenous chemical agents, distorting the DNA helix and interfering with replication and transcription
• DNA-protein crosslinks can occur when radiation induces covalent bonds between DNA and nearby proteins, hindering DNA metabolism and repair
• Clustered DNA damage refers to the formation of multiple types of DNA lesions within a short stretch of DNA, which can be more challenging to repair accurately

Cellular Response to Radiation

• Cell cycle arrest occurs in response to DNA damage, allowing time for repair before progression to the next phase of the cell cycle
  • G1 checkpoint prevents cells with damaged DNA from entering S phase
  • G2 checkpoint prevents cells with damaged DNA from entering mitosis
• DNA damage response (DDR) pathways are activated by the presence of DNA lesions and coordinate the cellular response
  • ATM (ataxia telangiectasia mutated) and ATR (ATM and Rad3-related) kinases are central regulators of the DDR
  • p53 is a key transcription factor that regulates cell cycle arrest, DNA repair, and apoptosis in response to DNA damage
• DNA repair mechanisms are activated to detect and repair various types of DNA lesions (covered in more detail in a later section)
• Apoptosis may be triggered if the extent of DNA damage exceeds the cell's repair capacity, eliminating potentially harmful cells
• Senescence is a state of permanent cell cycle arrest that can be induced by persistent DNA damage, preventing the proliferation of damaged cells
• Bystander effect refers to the phenomenon where irradiated cells communicate stress signals to neighboring unirradiated cells, inducing DNA damage and other cellular responses

Genomic Mutations: Types and Consequences

• Point mutations involve the substitution, insertion, or deletion of a single nucleotide
  • Base substitutions can be transitions (purine to purine or pyrimidine to pyrimidine) or transversions (purine to pyrimidine or vice versa)
  • Insertions and deletions can cause frameshift mutations if the number of bases added or removed is not a multiple of three
• Chromosomal aberrations involve large-scale changes in chromosome structure or number
  • Deletions involve the loss of a portion of a chromosome
  • Duplications involve the repetition of a portion of a chromosome
  • Inversions occur when a segment of a chromosome is flipped 180 degrees
  • Translocations involve the exchange of genetic material between non-homologous chromosomes
• Aneuploidy refers to an abnormal number of chromosomes, which can arise from errors in cell division (nondisjunction) or chromosome loss
• Polyploidy refers to the presence of more than two complete sets of chromosomes, which can occur naturally or be induced by radiation or chemicals
• Gene amplification involves the selective increase in the copy number of specific genes, often associated with resistance to chemotherapy or radiation
• Microsatellite instability (MSI) refers to the expansion or contraction of short tandem repeat sequences due to defects in DNA mismatch repair
• Radiation-induced genomic instability can manifest as delayed mutations, chromosomal aberrations, or altered gene expression in the progeny of irradiated cells

Repair Mechanisms and Adaptive Responses

• Base excision repair (BER) corrects small base modifications, such as oxidation or deamination, by removing the damaged base and replacing it with the correct nucleotide
• Nucleotide excision repair (NER) removes bulky DNA adducts and UV-induced pyrimidine dimers by excising a short segment of the damaged strand and filling in the gap
• Mismatch repair (MMR) corrects base mismatches and small insertion/deletion loops that arise during DNA replication
• Single-strand break repair (SSBR) involves the detection and repair of SSBs through the action of poly(ADP-ribose) polymerase (PARP) and other enzymes
• Double-strand break repair occurs through two main pathways:
  • Homologous recombination (HR) uses the sister chromatid as a template to accurately repair DSBs in the S and G2 phases of the cell cycle
  • Non-homologous end joining (NHEJ) directly ligates the broken ends of a DSB, which can be error-prone and lead to small insertions or deletions
• Adaptive responses refer to the phenomenon where exposure to a low dose of radiation can induce cellular changes that protect against subsequent higher doses
  • Increased DNA repair capacity, antioxidant defense, and immune function have been observed in some adaptive responses
  • The existence and significance of adaptive responses in humans remain controversial and require further research

Dose-Response Relationships

• Linear no-threshold (LNT) model assumes that the risk of biological effects increases linearly with radiation dose, with no threshold below which there is no risk
  • LNT model is widely used for radiation protection purposes, but its validity at low doses is debated
• Linear-quadratic model describes the dose-response relationship for many biological endpoints, with both linear and quadratic components
  • The linear component dominates at low doses and is associated with single-hit events
  • The quadratic component becomes more significant at higher doses and is associated with two-hit events
• Threshold model assumes that there is a dose below which no biological effects occur, and the risk increases above this threshold
• Hormetic model proposes that low doses of radiation may have beneficial effects, such as stimulating repair mechanisms and immune function
• Dose rate effects refer to the observation that the biological consequences of a given dose may differ depending on the rate at which the dose is delivered
  • Lower dose rates generally have a lower biological impact compared to higher dose rates
• Fractionation effects occur when a total dose is split into smaller fractions delivered over time, allowing for cellular repair and repopulation between fractions
• Individual variability in radiation response can be influenced by factors such as age, sex, genetic background, and health status

Applications and Implications in Medicine

• Radiation therapy uses ionizing radiation to kill cancer cells and shrink tumors
  • External beam radiation therapy (EBRT) delivers radiation from an external source, such as a linear accelerator
  • Brachytherapy involves the placement of radioactive sources directly inside or near the tumor
• Diagnostic radiology employs various imaging techniques that use ionizing radiation to visualize internal structures
  • X-ray radiography, computed tomography (CT), and fluoroscopy are common diagnostic procedures
  • Optimization of imaging protocols and dose reduction techniques are important to minimize patient exposure
• Nuclear medicine uses radioactive tracers for diagnostic imaging and targeted therapy
  • Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) provide functional and molecular information
  • Radionuclide therapy delivers targeted radiation to specific tissues or tumors using radiolabeled molecules
• Radiation protection in medicine aims to minimize the risks associated with medical exposure to ionizing radiation
  • Justification ensures that the benefits of a procedure outweigh the risks
  • Optimization involves using the lowest radiation dose necessary to achieve the desired diagnostic or therapeutic outcome
  • Dose limits are established for occupational and public exposure to radiation
• Personalized medicine approaches seek to tailor radiation therapy based on individual patient characteristics and tumor biology
  • Genetic profiling can identify patients with increased radiosensitivity or resistance
  • Targeted therapies can be combined with radiation to enhance tumor response and minimize side effects
• Long-term effects of medical radiation exposure, such as secondary cancers and cardiovascular disease, are important considerations in risk-benefit assessments
• Radiation-induced bystander effects and abscopal effects, where localized radiation induces systemic responses, are areas of active research in radiation oncology