DNA fragmentation in cultured cells exposed to high linear energy transfer radiation

Sammanfattning: The DNA double-strand break (DSB) is a critical lesion which, if not completely restored, can have serious biological consequences. The relative biological effectiveness (RBE) of many severe end-points are closely related to radiation quality, with increased effectiveness at elevated ionization density. Data presented provide information about the influence of radiation quality on the initial processes causing DNA damage, and the mechanisms leading to its restoration. Such information will increase the understanding of radiation action mechanisms in mammalian cells. Human cells were irradiated with accelerated ions having linear energy transfer (LET) values in the range 40-225 keV/μm, and 60Co-photons. Detailed analyses of the DNA fragment distributions were performed in the size-range 5 kilobasepairs to 6 megabasepairs by pulsed-field gel electrophoresis. A non-random fragmentation of DNA was evident, with an elevated number of small and medium-sized fragments for ion irradiation, and the total number of breaks increased by 80-110% when these fragments were included in the analyses. The RBE for DSB induction was 1.2-1.5. A two-fold increase of the number of breaks induced per nitrogen ion passing the cell nuclues was found when LET was increased from 80 to 225 keV/μm, indicating a possible role of particle track structure in DSB induction. Furthermore, the ability to repair DNA was closely related to radiation quality, with an increased proportion of unrejoined breaks for densely ionizing radiation. Surprisingly, the majority of breaks were rapidly rejoined even following exposure to high-LET radiation. The proportion of breaks restored by the slow phase showed a five-fold increase for the highest LET tested, compared with photons. The results presented nominates the complexity of breaks as one determining factor for reduced reparability reported following high-LET exposure.