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

iScience

Yosuke Tanaka¹  Yasufumi Murakami¹  Mai Hyodo²  Satoshi Tashiro³  Ken-ichi Yoshioka⁴  Hiroyuki Mano⁵  Hidetaka Torigoe⁶  Yasunori Horikoshi⁷  Mafuka Suzuki⁷  Yusuke Matsuno⁷ 

[1] Biological Science and Technology, Tokyo University of Science, Niijuku, Katsushika-ku, Tokyo 125-8585, Japan;Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan;Biological Science and Technology, Tokyo University of Science, Niijuku, Katsushika-ku, Tokyo 125-8585, Japan;Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan;Department of Cellular Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan;Division of Cellular Signaling, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan;Laboratory of Genome Stability Maintenance, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan;

关键词: Biological Sciences;    Cancer;    Cell Biology;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown