Clustered DNA double-strand break formation and the repair pathway following heavy-ion irradiation

Abstract

Photons, such as X- or γ-rays, induce DNA damage (distributed throughout the nucleus) as a result of low-density energy deposition. In contrast, particle irradiation with high linear energy transfer (LET) deposits high-density energy along the particle track. High-LET heavy-ion irradiation generates a greater number and more complex critical chromosomal aberrations, such as dicentrics and translocations, compared with X-ray or γ irradiation. In addition, the formation of >1000 bp deletions, which is rarely observed after X-ray irradiation, has been identified following high-LET heavy-ion irradiation. Previously, these chromosomal aberrations have been thought to be the result of misrepair of complex DNA lesions, defined as DNA damage through DNA double-strand breaks (DSBs) and single-strand breaks as well as base damage within 1–2 helical turns (<3–4 nm). However, because the scale of complex DNA lesions is less than a few nanometers, the large-scale chromosomal aberrations at a micrometer level cannot be simply explained by complex DNA lesions. Recently, we have demonstrated the existence of clustered DSBs along the particle track through the use of super-resolution microscopy. Furthermore, we have visualized high-level and frequent formation of DSBs at the chromosomal boundary following high-LET heavy-ion irradiation. In this review, we summarize the latest findings regarding the hallmarks of DNA damage structure and the repair pathway following heavy-ion irradiation. Furthermore, we discuss the mechanism through which high-LET heavy-ion irradiation may induce dicentrics, translocations and large deletions.

Genomic Instability and Carcinogenesis of Heavy Charged Particles Radiation: Clinical and Environmental Implications

“…In vivo studies have also shown that exposure to radiation can trigger carcinogenesis in subsequent generations. To date, numerous studies have shown that charged particle radiation is able to induce chromosomal aberrations and genomic instability in irradiated cells as well as their progenies [28,29,30]. Induction of mutation by heavy charged particles has been revealed by several studies [31,32].…”

Iron Ladies – How Desiccated Asexual Rotifer Adineta vaga Deal With X-Rays and Heavy Ions?

“…The ionization density in particle tracks is usually characterized by a physical parameter called Linear Energy Transfer (LET) describing the average energy (in keV) given up by a charged particle traversing a distance of 1 μm. High-Z charged particles (such as Fe ions) are high LET particles that will produce dense ionizations along their path while photons (like X-rays) which produce sparse ionizations are considered as low LET IR ( Joiner and van der Kogel, 2018 ; Hagiwara et al, 2019 ). Although a same dose of radiation leads to the same amount of ionizations, the differences in their spatial distribution is translated into different types of damages at biological level.…”

Interphase Cytogenetic Analysis of G0 Lymphocytes Exposed to α-Particles, C-Ions, and Protons Reveals their Enhanced Effectiveness for Localized Chromosome Shattering—A Critical Risk for Chromothripsis

“…This is mainly because the scale of clustered DNA damage is in the order of 10-30 bp, i.e., <3-4 nm, whereas the scale of chromosomal rearrangements is in the order of >1000 bp, i.e., >50-100 nm distance. To explain this discrepancy between clustered DNA lesions and chromosomal rearrangements in terms of scale, the possibility of mis-rejoining two DSBs belonging to distinct loci must be considered [39]. Indeed, this difference may be resolved by the existence of clustered DSBs in close proximity along the tracks of high-LET particle radiation.…”