DNA double-strand break induced by high-linear energy transfer irradiation

A DNA double-strand break induced by high-linear energy transfer irradiation, often abbreviated as "high LET-induced DSB," refers to one of the most severe forms of DNA damage caused when ionizing particles with dense energy deposition—such as heavy ions—traverse cellular nuclei. Unlike low LET radiation (e.g., X-rays), which causes more dispersed and generally less complex lesions that are efficiently repaired via base excision/nucleotide excision pathways, high LET radiation produces clustered and complex breaks along its track through chromatin. These clustered lesions are more difficult for cells to repair accurately due to their complexity and proximity on the genome; they frequently require coordinated action from multiple repair pathways including non-homologous end joining (NHEJ), homologous recombination (HR), microhomology-mediated end joining/TMEJ, among others[1][2]. Failure in efficient repair can result in chromosomal aberrations or cell death through apoptosis—a property exploited therapeutically in certain types of cancer radiotherapy but also posing risks for healthy tissue during accidental exposure or space travel[1][3]. This term does not refer to any specific protein/receptor/enzyme but rather describes an outcome/event at the molecular level following exposure.

Other names

High-LET-induced DNA double-strand breakRadiation-induced DSB (when context specifies high LET)Clustered DNA damage (in some contexts)

Not applicable for direct targeting; however, some drugs (e.g., PARP inhibitors) inhibit repair pathways activated in response to these breaks leading to synthetic lethality in cells with defective homologous recombination. Radioprotective agents may scavenge free radicals generated during irradiation, thereby reducing initial damage.