Radiation therapy is a key treatment for many cancers, but patient responses vary due to differences in genomic stability and DNA repair capacity. Increasing evidence highlights the role of Alu elements, the most abundant short interspersed nuclear elements in the human genome, as regulators of cellular stress responses. This review summarizes current knowledge on Alu biology, including their structure, retrotransposition, methylation, and expression, with a focus on their activation by ionizing radiation and their influence on DNA damage, repair pathways, gene regulation, and immune signaling. Radiation exposure has been shown to activate Alu elements, resulting in genomic destabilization, impaired repair, and pro-inflammatory responses. Consistent with this, Alu-associated mutations and microsatellite instability were observed at loci linked to key cancer genes (e.g., TP53, BRCA2), aligning with increased loss of heterozygosity and exon mutational burden. In addition, Alu hypomethylation further promotes microsatellite instability, recombination, defective repair, and is associated with therapeutic resistance. In parallel, circulating cell-free DNA fragments containing Alu sequences have also been correlated with delivered radiation dose and clinical toxicity, underscoring their potential as minimally invasive biomarkers. Taken together, these findings position Alu activation as both a mechanistic driver of radio-response heterogeneity and a minimally invasive biomarker for biodosimetry and toxicity risk stratification.
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