Replication-stress-associated DSBs induced by ionizing radiation risk genomic destabilization and associated clonal evolution
Yusuke Matsuno,
Mai Hyodo,
Mafuka Suzuki,
Yosuke Tanaka,
Yasunori Horikoshi,
Yasufumi Murakami,
Hidetaka Torigoe,
Hiroyuki Mano,
Satoshi Tashiro,
Ken-ichi Yoshioka
Affiliations
Yusuke Matsuno
Laboratory of Genome Stability Maintenance, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
Mai Hyodo
Laboratory of Genome Stability Maintenance, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Biological Science and Technology, Tokyo University of Science, Niijuku, Katsushika-ku, Tokyo 125-8585, Japan
Mafuka Suzuki
Laboratory of Genome Stability Maintenance, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Biological Science and Technology, Tokyo University of Science, Niijuku, Katsushika-ku, Tokyo 125-8585, Japan
Yosuke Tanaka
Division of Cellular Signaling, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
Yasunori Horikoshi
Department of Cellular Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
Yasufumi Murakami
Biological Science and Technology, Tokyo University of Science, Niijuku, Katsushika-ku, Tokyo 125-8585, Japan
Hidetaka Torigoe
Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
Hiroyuki Mano
Division of Cellular Signaling, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
Satoshi Tashiro
Department of Cellular Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
Ken-ichi Yoshioka
Laboratory of Genome Stability Maintenance, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Corresponding author
Summary: 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.
