期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 21, 期 18, 页码 -出版社
MDPI
DOI: 10.3390/ijms21186602
关键词
DNA double-strand breaks; high linear energy transfer; alpha particles; homologous recombination; live-cell microscopy; nonhomologous DNA end-joining
资金
- Technologie stichting STW [13577]
- Dutch Cancer Society
- Gravitation program CancerGenomiCs.nl from the Netherlands Organization for Scientific Research (NWO)
- Oncode Institute - Dutch Cancer Society
High-linear-energy-transfer (LET) radiation is more lethal than similar doses of low-LET radiation types, probably a result of the condensed energy deposition pattern of high-LET radiation. Here, we compare high-LET alpha-particle to low-LET X-ray irradiation and monitor double-strand break (DSB) processing. Live-cell microscopy was used to monitor DNA double-strand breaks (DSBs), marked by p53-binding protein 1 (53BP1). In addition, the accumulation of the endogenous 53BP1 and replication protein A (RPA) DSB processing proteins was analyzed by immunofluorescence. In contrast to alpha-particle-induced 53BP1 foci, X-ray-induced foci were resolved quickly and more dynamically as they showed an increase in 53BP1 protein accumulation and size. In addition, the number of individual 53BP1 and RPA foci was higher after X-ray irradiation, while focus intensity was higher after alpha-particle irradiation. Interestingly, 53BP1 foci induced by alpha-particles contained multiple RPA foci, suggesting multiple individual resection events, which was not observed after X-ray irradiation. We conclude that high-LET alpha-particles cause closely interspaced DSBs leading to high local concentrations of repair proteins. Our results point toward a change in DNA damage processing toward DNA end-resection and homologous recombination, possibly due to the depletion of soluble protein in the nucleoplasm. The combination of closely interspaced DSBs and perturbed DNA damage processing could be an explanation for the increased relative biological effectiveness (RBE) of high-LET alpha-particles compared to X-ray irradiation.
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