Replication-stress-associated DSBs induced by ionizing radiation risk genomic destabilization and associated clonal evolution

Exposure to ionizing radiation is associated with cancer risk. Although multiple types of DNA damage are caused by radiation, it remains unknown how this damage is associated with cancer risk. Here, we show that after repair of double-strand breaks (DSBs) directly caused by radiation (dir-DSBs), irradiated cells enter a state at higher risk of genomic destabilization due to accumulation of replication-stress-associated DSBs (rs-DSBs), ultimately resulting in clonal evolution of cells with abrogated defense systems. These effects were observed over broad ranges of radiation doses (0.25–2 Gy) and dose rates (1.39–909 mGy/min), but not upon high-dose irradiation, which caused permanent cell-cycle arrest. The resultant genomic destabilization also increased the risk of induction of single-nucleotide variants (SNVs), including radiation-associated SNVs, as well as structural alterations in chromosomes. Thus, the radiation-associated risk can be attributed to rs-DSB accumulation and resultant genomic destabilization. [Display omitted] •Replication-stress-associated DSBs accumulate after exposure to ionizing radiation•Such DSBs risk genomic destabilization and associated mutagenesis•The resulting genomic rearrangements and mutations lead to clonal evolution•The radiation-associated risks arise at wide ranges of radiation doses and dose rates Biological Sciences ; Cancer ; Cell Biology