Cell cycle-dependent radiosensitivity of CHO DNA repair mutants exposed to accelerated charged particles

Abstract

The two primary DNA double-strand break (DSB) repair pathways, non-homologous end joining (NHEJ) and homologous recombinational repair (HRR), play crucial roles in determining radiosensitivity throughout the cell cycle. Our study investigated mechanisms underlying cell cycle-dependent radiosensitivity following exposure to accelerated charged particles in DSB signaling and repair-deficient CHO mutant cell lines. We confirmed NHEJ-deficient V3 cells exhibit hyper-radiosensitivity across all phases, while HRR-deficient 51D1 cells display increased sensitivity in the typically radioresistant S/G2 phase following X- and gamma-rays. Exposures to accelerated 290 MeV/n C-12 and 500 MeV/n Fe-56 ions induced complex DNA damage that was not fully repaired by either pathway, leading to increased cell killing. HRR-deficient cells exhibited higher relative biological effectiveness (RBE) values for cell killing in G1 and S and levels of chromatid-type chromosomal aberrations were higher in HRR-deficient cells. Additionally, impaired G2-phase checkpoint activation in HRR-deficient cells contributed to mitotic entry with unresolved DNA damage. Our findings suggest that charged particles produce complex lesions that require coordinated repair by both major DSB repair pathways, and disruption of either pathway leads to increased radiosensitivity.