4.2 Radiation-induced damage to nucleic acids
4 min read•july 31, 2024
Radiation can wreak havoc on our , causing various types of damage. From simple base modifications to complex double-strand breaks, these lesions can have serious consequences for cells if left unrepaired.
Our bodies have evolved sophisticated repair mechanisms to deal with radiation-induced DNA damage. However, when these systems fail, the long-term effects can be severe, including genomic instability, cellular senescence, and even cancer.
Radiation-induced DNA lesions
Types and Frequencies of DNA Lesions
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- Radiation induces various DNA lesions including base modifications, sugar modifications, DNA-protein crosslinks, single-strand breaks (SSBs), and double-strand breaks (DSBs)
- Base modifications occur most frequently at ~1000 lesions per Gy of
- Involve oxidation, deamination, and alkylation of DNA bases
- Sugar modifications happen at 600-1000 lesions per Gy
- Include oxidation and fragmentation of the deoxyribose backbone
- DNA-protein crosslinks form at 150 lesions per Gy
- Result from radiation-induced covalent bonds between DNA and nearby proteins
- Single-strand breaks (SSBs) occur at ~1000 per Gy
- Double-strand breaks (DSBs) happen less often at ~40 per Gy
- Lesion frequencies vary based on radiation type/energy, cellular environment, and DNA conformation
Factors Influencing DNA Damage
- Radiation type impacts damage patterns
- High radiation (alpha particles) produces more complex DSBs
- Low LET radiation (X-rays, gamma rays) causes more dispersed damage
- Cellular oxygen levels affect damage
- Higher oxygen increases free radical production and oxidative DNA damage
- Hypoxic conditions can make cells more radioresistant
- DNA conformation influences damage susceptibility
- Tightly packed heterochromatin protects DNA more than loose euchromatin
- Actively transcribed genes may be more vulnerable to radiation damage
- Cell cycle phase affects damage and repair capacity
- S phase cells are most radiosensitive due to open chromatin during replication
- G0/G1 phase cells are more radioresistant
DNA Breaks: Formation and Consequences
Single-Strand Break (SSB) Formation and Effects
- SSBs form when radiation breaks one DNA strand
- Caused by direct ionization or free radical attack
- SSBs can lead to replication fork collapse during DNA synthesis
- May result in more severe double-strand breaks if unrepaired
- SSB repair involves several steps:
- Detection by PARP1 enzyme
- End processing to remove damaged nucleotides
- Gap filling by DNA polymerase
- Nick sealing by DNA ligase
- Unrepaired SSBs can cause:
- Stalled replication forks
- Transcription blockage
- Eventual conversion to DSBs
Double-Strand Break (DSB) Formation and Consequences
- DSBs involve breakage of both DNA strands
- Can occur simultaneously or from two nearby SSBs on opposite strands
- DSBs are considered most lethal form of DNA damage
- Lead to chromosomal aberrations, cell cycle arrest, and if unrepaired
- DSB complexity varies
- Simple DSBs have clean DNA ends
- Complex DSBs have additional damage within 1-2 helical turns (clustered lesions)
- High-LET radiation produces more complex, difficult-to-repair DSBs
- DSBs trigger DNA damage response (DDR) signaling
- Activate ATM and DNA-PK kinases
- Phosphorylate histone H2AX to mark damage sites
- Recruit repair factors like 53BP1 and BRCA1
- Unrepaired DSBs can result in:
- Chromosomal translocations
- Large deletions or duplications
- Mitotic catastrophe and cell death
DNA Repair Mechanisms
Excision Repair Pathways
- Base Excision Repair (BER) addresses small base modifications
- Glycosylase removes damaged base
- AP endonuclease cleaves DNA backbone
- DNA polymerase fills gap
- DNA ligase seals nick
- Nucleotide Excision Repair (NER) handles bulky lesions and crosslinks
- XPC-RAD23B or UV-DDB recognizes damage
- TFIIH unwinds DNA around lesion
- XPF-ERCC1 and XPG nucleases excise damaged region
- DNA polymerase and ligase fill and seal gap
- Mismatch Repair (MMR) corrects base mismatches and small loops
- MutS proteins recognize mismatch
- MutL proteins recruit exonuclease
- Exonuclease removes error-containing strand
- DNA polymerase and ligase restore correct sequence
Double-Strand Break Repair Pathways
- (HR) uses sister chromatid template
- MRN complex and CtIP resect DNA ends
- RPA coats single-stranded DNA
- BRCA2 loads RAD51 to form nucleoprotein filament
- RAD51 filament invades homologous template
- DNA synthesis and resolution of intermediates
- (NHEJ) directly ligates broken ends
- Ku70/80 binds DNA ends
- DNA-PKcs is recruited and activated
- Artemis processes DNA ends if necessary
- XRCC4-XLF-Ligase IV complex seals break
- Choice between HR and NHEJ influenced by:
- Cell cycle phase (HR in S/G2, NHEJ throughout)
- Chromatin structure
- Complexity of DNA damage
Unrepaired DNA Damage: Long-Term Effects
Genomic Instability and Cellular Senescence
- Unrepaired/misrepaired DNA damage leads to genomic instability
- Increased mutations, chromosomal aberrations, and aneuploidy
- Persistent DNA damage triggers cellular senescence
- Permanent cell cycle arrest contributing to tissue aging
- Senescent cells secrete inflammatory factors (SASP)
- Radiation-induced bystander effects amplify damage
- Non-irradiated cells show DNA damage and instability
- Mediated by secreted factors and gap junctions
- Epigenetic alterations persist long-term after exposure
- Changes in DNA methylation patterns
- Altered histone modifications (acetylation, methylation)
Carcinogenesis and Hereditary Effects
- Misrepaired DSBs can cause chromosomal rearrangements
- Translocations activate oncogenes (BCR-ABL in leukemia)
- Deletions inactivate tumor suppressors (p53)
- Radiation-induced mutations in critical genes promote cancer
- DNA repair genes (BRCA1/2, MLH1)
- Cell cycle regulators (RB1, CDKN2A)
- Apoptosis mediators (BAX, BCL2)
- Transgenerational effects may occur through:
- Epigenetic modifications in germ cells
- Persistent genomic instability in offspring
- Increased cancer risk in irradiated populations
- Atomic bomb survivors show elevated rates of leukemia and solid tumors
- Radiotherapy patients have higher risk of secondary cancers
Key Terms to Review (18)
Apoptosis: Apoptosis is a programmed form of cell death that occurs in a controlled manner, allowing the body to eliminate damaged or unnecessary cells without causing inflammation. This process is crucial for maintaining homeostasis, development, and tissue maintenance, and plays a significant role in response to cellular stress, including damage from radiation.
Cell Survival Curve: A cell survival curve is a graphical representation that depicts the relationship between the dose of radiation exposure and the proportion of surviving cells following that exposure. This curve helps illustrate how various factors, such as the type of radiation, the biological characteristics of cells, and the timing of exposure, influence cellular response and damage. Understanding these curves provides insights into radiation-induced damage, cellular repair mechanisms, and overall radiosensitivity.
Comet assay: The comet assay, also known as single-cell gel electrophoresis, is a sensitive and straightforward technique used to detect DNA damage in individual cells. This method allows researchers to visualize DNA strand breaks and other forms of nucleic acid damage caused by various factors, including radiation. The assay connects to understanding how radiation induces damage to DNA, the specific types of damage it causes, the mechanisms behind DNA repair, and the consequences of misrepair leading to chromosomal abnormalities.
DNA: DNA, or deoxyribonucleic acid, is the hereditary material in humans and almost all other organisms, encoding the genetic instructions used in the development and functioning of living things. In the context of radiation-induced damage, DNA plays a crucial role as it is susceptible to alterations caused by ionizing radiation, leading to mutations and potential cell dysfunction or death.
Double-strand break: A double-strand break is a type of DNA damage where both strands of the DNA helix are severed, leading to significant disruptions in genetic information. This form of damage is particularly critical because it can lead to chromosomal instability and various cellular outcomes, including mutations and cell death. Understanding double-strand breaks is crucial in the context of radiation-induced damage, as these breaks can arise from exposure to ionizing radiation and can initiate complex repair processes that are pivotal in maintaining genomic integrity.
Homologous Recombination: Homologous recombination is a fundamental genetic process that involves the exchange of genetic material between similar or identical DNA sequences, usually during DNA repair or meiosis. This mechanism is crucial for fixing double-strand breaks in DNA, which can be caused by radiation-induced damage, and plays a significant role in maintaining genomic stability and diversity.
Ionizing Radiation: Ionizing radiation refers to high-energy radiation that has enough energy to remove tightly bound electrons from atoms, thus creating ions. This type of radiation can interact with matter, leading to various biological effects, which are crucial in understanding the impact on living tissues and the environment.
Linear Energy Transfer (LET): Linear Energy Transfer (LET) is a measure of the energy released by ionizing radiation as it travels through matter, typically expressed in units of keV/µm. It describes how much energy is deposited along a track of radiation, which has significant implications for understanding the biological effects of different types of radiation, their interaction with cellular components, and their potential for causing damage to DNA and tissues.
Mutagenesis: Mutagenesis is the process by which genetic information of an organism is changed, resulting in mutations. This change can be triggered by various factors, including radiation, which can lead to direct and indirect effects on cellular structures and functions. Understanding mutagenesis helps connect the dots between radiation exposure and its biological consequences, including damage to nucleic acids and potential transgenerational effects.
Non-homologous end joining: Non-homologous end joining (NHEJ) is a crucial DNA repair mechanism that directly joins broken ends of double-strand DNA breaks without the need for a homologous template. This pathway is vital in maintaining genomic stability, especially following radiation-induced damage that results in breaks in the DNA. By rapidly repairing these breaks, NHEJ plays a significant role in preventing mutations and chromosomal aberrations.
Non-ionizing radiation: Non-ionizing radiation refers to types of electromagnetic radiation that do not carry enough energy to ionize atoms or molecules, meaning they do not have sufficient energy to remove tightly bound electrons. This category of radiation includes visible light, radio waves, microwaves, and ultraviolet (UV) radiation. Although non-ionizing radiation is generally considered less harmful than ionizing radiation, it can still have biological effects and is relevant in the study of various phenomena such as cellular response mechanisms and potential environmental impacts.
Radiation resistance: Radiation resistance refers to the ability of biological cells or organisms to withstand or repair damage caused by exposure to ionizing radiation. This characteristic is crucial for maintaining cellular integrity and function after radiation exposure, as it directly affects how well organisms can survive in environments with high radiation levels. Understanding radiation resistance is vital for assessing the potential risks of radiation exposure and developing protective measures in both medical and environmental contexts.
Radiation Sensitivity: Radiation sensitivity refers to the degree to which biological tissues or cells are affected by exposure to ionizing radiation. This sensitivity varies among different types of cells and organisms, influencing their likelihood of experiencing damage such as mutations, cell death, or other detrimental effects. Understanding radiation sensitivity is crucial for evaluating how different cells respond to radiation therapy and assessing risks associated with radiation exposure.
Radiobiological Effectiveness: Radiobiological effectiveness (RBE) refers to the relative capability of different types of ionizing radiation to cause biological damage, particularly in terms of inducing cell killing or mutations. This concept is essential for understanding how various radiation types, like alpha particles or gamma rays, affect nucleic acids and other cellular components differently. The RBE is influenced by factors such as the radiation's energy, type, and the biological context in which it operates.
RNA: RNA, or ribonucleic acid, is a molecule essential for various biological roles, particularly in coding, decoding, regulation, and expression of genes. It is primarily involved in the synthesis of proteins from genetic information encoded in DNA and plays a crucial role in the cellular response to radiation-induced damage to nucleic acids, as it can influence repair mechanisms and gene expression after such events.
Single-strand break: A single-strand break is a type of DNA damage where one of the two strands of the DNA helix is severed, leaving the other strand intact. This form of damage can disrupt normal cellular functions and may result from exposure to radiation or certain chemicals, impacting the integrity of nucleic acids, leading to various types of DNA damage and potentially resulting in mutations during cell replication.
Target Theory: Target theory is a concept that explains how radiation interacts with biological systems by identifying specific cellular targets, such as DNA or other critical molecules, that when damaged, lead to biological effects. This theory emphasizes the importance of direct hits to these targets in producing radiation-induced damage and highlights the relationship between the type of radiation, energy transfer, and the severity of biological consequences.
γ-h2ax foci: γ-h2ax foci are discrete nuclear structures that form in response to DNA double-strand breaks, marking sites of damage for repair. They indicate the presence of phosphorylated histone H2AX, which is a crucial early step in the cellular response to radiation-induced DNA damage. Understanding γ-h2ax foci helps in studying how cells react to radiation and the types of DNA damage that can occur.