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

doi:10.1016/j.isci.2021.102313

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

iScience. 2021 Mar 15;24(4):102313. doi: 10.1016/j.isci.2021.102313. eCollection 2021 Apr 23.

Authors

Yusuke Matsuno^{1

2}, Mai Hyodo^{1

3}, Mafuka Suzuki^{1

3}, Yosuke Tanaka⁴, Yasunori Horikoshi⁵, Yasufumi Murakami³, Hidetaka Torigoe², Hiroyuki Mano⁴, Satoshi Tashiro⁵, Ken-Ichi Yoshioka¹

Affiliations

¹ Laboratory of Genome Stability Maintenance, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
² Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan.
³ Biological Science and Technology, Tokyo University of Science, Niijuku, Katsushika-ku, Tokyo 125-8585, Japan.
⁴ Division of Cellular Signaling, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
⁵ Department of Cellular Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.

Abstract

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.

Keywords: Biological Sciences; Cancer; Cell Biology.