5.3 Consequences of unrepaired DNA damage

DNA damage from radiation can wreak havoc on cells. When left unrepaired, it can lead to cell death, mutations, and genomic instability. These effects ripple through generations of cells, potentially causing cancer and other long-term health issues.

Understanding the consequences of unrepaired DNA damage is crucial for grasping radiation's impact on our bodies. From cell cycle disruption to epigenetic changes, these effects highlight why our DNA repair mechanisms are so important for maintaining cellular health and preventing disease.

DNA Damage Outcomes in Irradiated Cells

Cell Death and Mutation

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• Unrepaired DNA damage triggers cell death through apoptosis or necrosis depending on damage extent and type
• Mutations arise when damaged DNA replicates before repair alters gene expression or protein function
• Chromosomal aberrations result from unrepaired double-strand breaks leading to deletions, translocations, or fusions (Philadelphia chromosome in chronic myeloid leukemia)
• Genomic instability emerges characterized by increased genetic alterations in subsequent cell generations

Cell Cycle Disruption and Epigenetic Changes

• Cell cycle arrest occurs at checkpoints preventing damaged cells from dividing until repair completion or cell death initiation (G1/S and G2/M checkpoints)
• Senescence induces permanent cell cycle arrest in cells with persistent DNA damage
• Epigenetic changes affect gene expression due to unrepaired DNA damage altering DNA methylation patterns (hypermethylation of tumor suppressor genes)

DNA Damage, Genomic Instability, and Carcinogenesis

Genomic Instability and Cancer Hallmarks

• Unrepaired or misrepaired DNA damage leads to genomic instability increasing mutations and chromosomal aberrations
• Genomic instability drives accumulation of additional mutations necessary for carcinogenesis (mutator phenotype)
• Specific mutations in oncogenes or tumor suppressor genes initiate carcinogenic process (BRCA1/2 mutations in breast cancer)
• Chromosomal instability causes aneuploidy and structural abnormalities commonly observed in cancer cells (trisomy 21 in acute myeloid leukemia)

Telomere Dysfunction and Epigenetic Alterations

• Telomere dysfunction associated with genomic instability contributes to chromosomal fusions and breakage-fusion-bridge cycles promoting cancer progression
• Epigenetic alterations from DNA damage lead to aberrant gene expression patterns potentially contributing to carcinogenesis (hypermethylation of p16 tumor suppressor gene)
• Accumulation of DNA damage and genomic instability over time increases likelihood of cellular transformation and cancer development

Defective DNA Repair and Radiation Sensitivity

DNA Repair Deficiencies and Radiosensitivity

• Defects in DNA repair pathways (homologous recombination, non-homologous end joining) significantly increase cellular sensitivity to ionizing radiation
• Inherited DNA repair deficiency syndromes exhibit heightened radiosensitivity (Ataxia-telangiectasia, Nijmegen breakage syndrome)
• Impaired DNA repair accumulates unresolved DNA damage increasing likelihood of cell death or genomic instability following radiation exposure
• Defective DNA repair mechanisms lower threshold for radiation-induced carcinogenesis as damaged DNA more likely misrepaired or replicated with errors

DNA Repair and Cancer Treatment

• Radiotherapy efficacy influenced by DNA repair capacity of tumor cells with deficient repair potentially enhancing tumor radiosensitivity
• DNA repair gene polymorphisms contribute to individual differences in radiation sensitivity and cancer susceptibility (XRCC1 polymorphisms)
• Understanding DNA repair mechanism status in tumors informs personalized radiotherapy strategies and predicts treatment outcomes (PARP inhibitors in BRCA-deficient tumors)

Long-Term Effects of Radiation-Induced DNA Damage

Cellular Dysfunction and Genomic Instability

• Persistent DNA damage chronically activates DNA damage response pathways altering cellular metabolism and energy allocation
• Accumulating mutations from unrepaired or misrepaired DNA damage progressively impair cellular function and tissue homeostasis
• Radiation-induced genomic instability transmits to daughter cells affecting function of entire cell populations or tissues long after initial exposure
• Epigenetic changes alter gene expression patterns leading to long-term changes in cellular phenotype and function (radiation-induced hypomethylation of repetitive elements)

Tissue Aging and Bystander Effects

• Cellular senescence induced by persistent DNA damage contributes to tissue aging and age-related pathologies through pro-inflammatory factor secretion (senescence-associated secretory phenotype)
• Radiation-induced bystander effects cause DNA damage and functional changes in non-irradiated cells amplifying long-term impact on tissue function
• Chronic oxidative stress associated with radiation-induced DNA damage leads to cumulative cellular dysfunction contributing to various pathological conditions (radiation-induced fibrosis)