Whole-genome sequencing (WGS) of human tumors and normal cells exposed to various carcinogens has revealed distinct mutational patterns that provide deep insights into the DNA damage and repair processes. Although ionizing radiation (IR) is conventionally known as a strong carcinogen, its genome-wide mutational impacts have not been comprehensively investigated at the single-nucleotide level. Here, we explored the mutational landscape of normal single-cells after exposure to the various levels of IR. On average, 1 Gy of IR exposure generated ~16 mutational events with a spectrum consisting of predominantly small nucleotide deletions and a few characteristic structural variations. In ~30% of the post-irradiated cells, complex genomic rearrangements, such as chromoplexy, chromothripsis, and breakage-fusion-bridge cycles, were resulted, indicating the stochastic and chaotic nature of DNA repair in the presence of the massive number of concurrent DNA double-strand breaks. These mutational signatures were confirmed in the genomes of 22 IR-induced secondary malignancies. With high-resolution genomic snapshots of irradiated cells, our findings provide deep insights into how IR-induced DNA damage and subsequent repair processes operate in mammalian cells.

中文翻译：

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电离辐射的突变影响和特征

暴露于各种致癌物的人类肿瘤和正常细胞的全基因组测序（WGS）显示出独特的突变模式，可提供对DNA损伤和修复过程的深刻见解。尽管电离辐射（IR）通常被称为强致癌物，但尚未在单核苷酸水平上全面研究其全基因组突变影响。在这里，我们探索了正常的单细胞在暴露于不同水平的IR后的突变态势。平均而言，1 Gy的IR暴露会产生〜16个突变事件，其光谱主要由小的核苷酸缺失和一些特征性的结构变异组成。在约30％的辐照后细胞中，导致复杂的基因组重排，例如染色体异常，染色体异常和断裂融合桥循环，表明存在大量并发DNA双链断裂时DNA修复的随机性和混乱性。这些突变特征在22个IR诱导的继发性恶性肿瘤的基因组中得到证实。借助辐射细胞的高分辨率基因组快照，我们的发现为深入了解IR诱导的DNA损伤及其后续修复过程在哺乳动物细胞中的运作方式提供了深刻的见解。