Promoted Misrejoining of X-ray Radiation-induced DNA Double-Strand Breaks in Novel DNA Ligase IV-Deficient Mouse...

DNA double-strand breaks (DSBs) are the most severe type of DNA damage in living organisms and are primarily repaired by two pathways: non-homologous end joining (NHEJ) and homologous recombination (HR). DNA ligase IV (LIG4) is essential for the final step of NHEJ, where it facilitates the rejoining of DSBs. Loss-of-function mutations in the LIG4 gene result in LIG4 syndrome, a condition characterized by combined immunodeficiency, developmental delay, microcephaly and radiosensitivity. In this study, we investigated cellular senescence, radiosensitivity, and X-ray radiation-induced chromosome aberrations induced in newly developed Lig4 mutant (Lig4W447C/W447C) mouse cells. The results showed that Lig4W447C/W447C cells exhibited accelerated cellular senescence, possibly due to increased accumulation of spontaneous DSBs. Radiosensitivity assays revealed that Lig4W447C/W447C cells were four times more radiosensitive than wild-type cells. Moreover, analysis of both X-ray radiation-induced chromatid-type and chromosome-type aberrations revealed that both break-type aberrations (e.g., fragments) and exchange-type aberrations (e.g., dicentrics) were increased in Lig4W447C/W447C cells compared to wild-type cells. These results suggest that in addition to causing inefficient DNA break, end-joining, the novel mutation in Lig4 may promote misrejoining of X-ray radiation-induced DSBs.