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

• Published in: Journal of radiation research Vol. 60; no. 1; pp. 69 - 79
• Main Authors: Hagiwara, Yoshihiko, Oike, Takahiro, Niimi, Atsuko, Yamauchi, Motohiro, Sato, Hiro, Limsirichaikul, Siripan, Held, Kathryn D, Nakano, Takashi, Shibata, Atsushi
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.01.2019
• Subjects: Aberration; Cancer; Chromosome abnormalities; Density; DNA; DNA damage; Energy transfer; Energy transformation; Gamma irradiation; Gamma rays; Genetic aspects; Heavy ions; Ion irradiation; Ionizing radiation; Lesions; Linear energy transfer (LET); Microscopy; Observations; Particle tracking; Radiation damage; Radiation exposure; Radiotherapy; Review; X ray irradiation; Japan; radiotherapy; cancer treatment; heavy-ion irradiation; DNA double-strand breaks; super-resolution microscopy; DSB repair pathway
• ISSN: 0449-3060; 1349-9157; 1349-9157
• DOI: 10.1093/jrr/rry096

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.