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由电离辐射诱导的与复制应激相关的双链断裂存在基因组不稳定和相关克隆进化的风险。

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

作者信息

Matsuno Yusuke, Hyodo Mai, Suzuki Mafuka, Tanaka Yosuke, Horikoshi Yasunori, Murakami Yasufumi, Torigoe Hidetaka, Mano Hiroyuki, Tashiro Satoshi, Yoshioka Ken-Ichi

机构信息

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.

出版信息

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

DOI:10.1016/j.isci.2021.102313
PMID:33870130
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8042347/
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.

摘要

暴露于电离辐射与癌症风险相关。尽管辐射会导致多种类型的DNA损伤，但这种损伤与癌症风险之间的关联仍不清楚。在此，我们表明，在修复由辐射直接引起的双链断裂（dir-DSBs）后，受辐射细胞会进入一种由于复制应激相关双链断裂（rs-DSBs）积累而导致基因组不稳定风险更高的状态，最终导致防御系统被破坏的细胞发生克隆进化。在广泛的辐射剂量范围（0.25 - 2 Gy）和剂量率范围（1.39 - 909 mGy/分钟）内均观察到了这些效应，但在导致永久性细胞周期停滞的高剂量照射下未观察到。由此产生的基因组不稳定还增加了单核苷酸变异（SNV）的诱导风险，包括与辐射相关的SNV，以及染色体结构改变。因此，辐射相关风险可归因于rs-DSB积累和由此导致的基因组不稳定。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/97fa/8042347/0b6d3db4ef8a/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/97fa/8042347/f030cf332859/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/97fa/8042347/05c5ef7aa421/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/97fa/8042347/ba268f6a46fe/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/97fa/8042347/f4c3dbd2cef2/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/97fa/8042347/5473d4eed5b9/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/97fa/8042347/9e535840bc58/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/97fa/8042347/0b6d3db4ef8a/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/97fa/8042347/f030cf332859/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/97fa/8042347/05c5ef7aa421/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/97fa/8042347/ba268f6a46fe/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/97fa/8042347/f4c3dbd2cef2/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/97fa/8042347/5473d4eed5b9/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/97fa/8042347/9e535840bc58/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/97fa/8042347/0b6d3db4ef8a/gr6.jpg

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