7.2 Mechanisms of chromosomal damage and misrepair
4 min read•july 31, 2024
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
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- 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 , , base modifications, and DNA-protein crosslinks
- of radiation influences spatial distribution and complexity of 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 and
- 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
DNA Double-Strand Breaks in Aberrations
DSB Formation and Consequences
- DNA double-strand breaks (DSBs) form most critical lesions for
- 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 ()
- Persistent DSBs can result in:
- Chromosome fragmentation
- Chromosome loss leading to
- Cell death through
- DSB complexity influences repair pathway choice and efficiency
- Simple DSBs more easily repaired by (NHEJ)
- Complex DSBs may require (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: 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 (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 ()
- 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
Key Terms to Review (25)
Aneuploidy: Aneuploidy refers to the presence of an abnormal number of chromosomes in a cell, which can result from errors in cell division. This condition can lead to various health issues, including developmental disorders and cancer, as it disrupts the normal balance of gene dosage and cellular function. The mechanisms causing aneuploidy often involve chromosomal damage and misrepair, as well as failures during the checkpoints of the cell cycle.
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.
Base Excision Repair: Base excision repair (BER) is a crucial DNA repair mechanism that removes and replaces damaged or non-canonical bases in DNA. This process is vital for maintaining genomic integrity, as it specifically targets small-scale lesions like oxidized, alkylated, or deaminated bases, which can lead to mutations if left unrepaired. BER works through a series of coordinated steps involving DNA glycosylases, which recognize and excise the faulty base, followed by the recruitment of other enzymes to fill in the gap and restore the correct DNA sequence.
Bystander effects: Bystander effects refer to biological responses observed in cells that were not directly irradiated but are affected by signals from neighboring cells that have received radiation exposure. This phenomenon highlights the complex intercellular communication that can lead to genomic instability and cancer induction in adjacent, unexposed cells, emphasizing its importance in understanding mechanisms of chromosomal damage and the broader implications for health risks associated with radiation exposure.
Carcinogenesis: Carcinogenesis is the process by which normal cells transform into cancer cells through a series of genetic mutations and cellular changes. This process can be triggered by various factors, including exposure to radiation, which can damage cellular components such as proteins, lipids, and DNA, ultimately leading to uncontrolled cell growth and tumor formation.
Cell cycle checkpoints: Cell cycle checkpoints are regulatory mechanisms in the cell cycle that ensure the proper progression of cell division by monitoring and verifying whether the processes at each stage have been accurately completed. These checkpoints help prevent the replication of damaged DNA and ensure that cells do not proceed to division until they are ready, which is crucial for maintaining genomic stability and preventing diseases such as cancer. Their importance extends to understanding how chromosomal damage occurs and is misrepaired, as well as their role in personalized treatment strategies in radiotherapy.
Chromosomal aberrations: Chromosomal aberrations are structural alterations in chromosomes that can lead to genetic abnormalities. These changes can occur due to various factors, including radiation exposure or chemical agents, and can result in consequences such as cancer or developmental disorders if the damage remains unrepaired. Understanding these aberrations is crucial for grasping the long-term effects of DNA damage and the mechanisms that lead to genomic instability.
Clustered DNA Damage: Clustered DNA damage refers to the type of DNA damage that occurs when multiple lesions are found in close proximity on the DNA molecule, often as a result of radiation exposure. This form of damage is significant because it can lead to complex repair challenges, contributing to chromosomal abnormalities and mutations when misrepaired. Understanding clustered DNA damage is crucial for grasping the various types of DNA damage from radiation and the mechanisms behind chromosomal damage and misrepair.
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.
Double-strand breaks: Double-strand breaks (DSBs) are severe forms of DNA damage where both strands of the DNA helix are broken. This type of damage can lead to significant cellular consequences if not repaired properly, impacting various biological processes such as cell survival, genomic stability, and the integrity of genetic information.
Fish analysis: Fish analysis, or fluorescence in situ hybridization (FISH), is a cytogenetic technique that allows for the visualization of specific DNA sequences on chromosomes. This method uses fluorescent probes that bind to particular parts of the chromosome, enabling researchers to identify chromosomal abnormalities, gene mapping, and the structural organization of chromosomes, which are essential for understanding mechanisms of chromosomal damage and misrepair.
Gamma rays: Gamma rays are high-energy electromagnetic radiation emitted from the nucleus of radioactive atoms, possessing extremely short wavelengths and high penetration power. Due to their ability to ionize matter, they play a significant role in the study of radiobiology, especially in understanding radiation interactions, cellular damage, and cancer risk assessment.
Genomic Instability: Genomic instability refers to the increased tendency of an organism's DNA to acquire mutations, leading to alterations in the genome that can have significant biological consequences. This instability is often a result of DNA damage, and when not properly repaired, can contribute to various diseases, including cancer, by disrupting normal cellular functions and promoting tumorigenesis.
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.
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.
Microhomology-mediated end joining: Microhomology-mediated end joining (MMEJ) is a DNA repair mechanism that utilizes short, homologous sequences to facilitate the joining of broken DNA ends. This process often occurs when double-strand breaks in DNA are not repaired through the more accurate homologous recombination or non-homologous end joining pathways, leading to potential chromosomal rearrangements and instability.
Mitotic catastrophe: Mitotic catastrophe is a type of cell death that occurs when cells experience severe damage during mitosis, leading to an inability to complete cell division properly. This event is often triggered by chromosomal damage and misrepair, resulting in the formation of cells with an abnormal number of chromosomes, which can contribute to genomic instability and tumorigenesis. It plays a critical role in understanding how cancer cells respond to radiation and chemotherapy.
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.
Nucleotide excision repair: Nucleotide excision repair (NER) is a DNA repair mechanism that removes damaged DNA segments and replaces them with correctly synthesized nucleotides. This process is crucial for maintaining genomic integrity by recognizing and repairing a variety of DNA lesions, particularly those caused by environmental factors such as UV radiation. NER is significant because it connects to various cellular responses to DNA damage, the understanding of chromosomal anomalies, and the pathways through which radiation exposure can lead to cancer.
Philadelphia Chromosome: The Philadelphia chromosome is an abnormal chromosome 22 that results from a translocation between chromosomes 9 and 22, specifically t(9;22)(q34;q11). This genetic alteration is commonly associated with chronic myeloid leukemia (CML) and serves as a critical marker for diagnosis and treatment. The presence of this chromosome is a prime example of how chromosomal damage can lead to malignancy and highlights the complexities of chromosomal aberrations.
Radiation-induced mutation: Radiation-induced mutation refers to the changes in DNA sequence that occur as a result of exposure to ionizing radiation. This process can lead to alterations in genetic material, potentially resulting in various consequences, including cancer or inherited genetic disorders. Understanding how these mutations occur and their impact is essential for assessing biological risks of radiation exposure and evaluating ecological effects on organisms in their environments.
Single-strand breaks: Single-strand breaks are disruptions that occur in one of the two strands of the DNA helix, leading to a break in the sugar-phosphate backbone. These breaks can arise from various sources, including ionizing radiation and chemical agents. Understanding single-strand breaks is crucial, as they can be repaired through specific cellular mechanisms, and their consequences can lead to further DNA damage or genomic instability if not addressed promptly.
Tumorigenesis: Tumorigenesis is the process through which normal cells undergo transformation into cancerous cells, leading to the formation of tumors. This complex sequence involves genetic mutations, disrupted cellular signaling, and alterations in cell growth regulation, ultimately resulting in uncontrolled proliferation. Understanding tumorigenesis is critical as it connects to the consequences of DNA damage, mechanisms of chromosomal misrepair, the regulation of the cell cycle, and how radiation can initiate carcinogenic processes.
X-rays: X-rays are a form of electromagnetic radiation with wavelengths shorter than ultraviolet light, allowing them to penetrate various materials, including human tissue. This property makes x-rays valuable in medical imaging and diagnostic procedures, while also posing risks related to chromosomal damage, mutations, and the biological effects of radiation exposure.