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Quantitative and qualitative mutational impact of ionizing radiation on normal cells.

ABSTRACT: The comprehensive genomic impact of ionizing radiation (IR), a carcinogen, on healthy somatic cells remains unclear. Using large-scale whole-genome sequencing (WGS) of clones expanded from irradiated murine and human single cells, we revealed that IR induces a characteristic spectrum of short insertions or deletions (indels) and structural variations (SVs), including balanced inversions, translocations, composite SVs (deletion-insertion, deletion-inversion, and deletion-translocation composites), and complex genomic rearrangements (CGRs), including chromoplexy, chromothripsis, and SV by breakage-fusion-bridge cycles. Our findings suggest that 1 Gy IR exposure causes an average of 2.33 mutational events per Gb genome, comprising 2.15 indels, 0.17 SVs, and 0.01 CGRs, despite a high level of inter-cellular stochasticity. The mutational burden was dependent on total irradiation dose, regardless of dose rate or cell type. The findings were further validated in IR-induced secondary cancers and single cells without clonalization. Overall, our study highlights a comprehensive and clear picture of IR effects on normal mammalian genomes.

SUBMITTER: Youk J

PROVIDER: S-EPMC10879144 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Quantitative and qualitative mutational impact of ionizing radiation on normal cells.

Youk Jeonghwan J Kwon Hyun Woo HW Lim Joonoh J Kim Eunji E Kim Taewoo T Kim Ryul R Park Seongyeol S Yi Kijong K Nam Chang Hyun CH Jeon Sara S An Yohan Y Choi Jinwook J Na Hyelin H Lee Eon-Seok ES Cho Youngwon Y Min Dong-Wook DW Kim HyoJin H Kang Yeong-Rok YR Choi Si Ho SH Bae Min Ji MJ Lee Chang Geun CG Kim Joon-Goon JG Kim Young Seo YS Yu Tosol T Lee Won-Chul WC Shin Jong-Yeon JY Lee Dong Soo DS Kim Tae-You TY Ku Taeyun T Kim Su Yeon SY Lee Joo-Hyeon JH Koo Bon-Kyoung BK Lee Hyunsook H Yi On Vox OV Han Eon Chul EC Chang Ji Hyun JH Kim Kyung Su KS Son Tae Gen TG Ju Young Seok YS

Cell genomics 20240201 2

The comprehensive genomic impact of ionizing radiation (IR), a carcinogen, on healthy somatic cells remains unclear. Using large-scale whole-genome sequencing (WGS) of clones expanded from irradiated murine and human single cells, we revealed that IR induces a characteristic spectrum of short insertions or deletions (indels) and structural variations (SVs), including balanced inversions, translocations, composite SVs (deletion-insertion, deletion-inversion, and deletion-translocation composites) ...[more]

PMID: 38359788

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Project description:Whilst the cataractogenic potential of ionizing radiation has been known for over the past 120 years, little is known about radiation responses of lens cells. Our previous work was the first to evaluate the radiosensitivity of lens cells with the clonogenic assay, documenting that the survival of HLEC1 human lens epithelial cells is comparable to that of WI-38 human lung fibroblasts. Moreover, HLEC1 cells were found to contain subsets where irradiation stimulates proliferation or facilitates formation of abortive colonies with fewer cells than human fibroblasts. This study aims to gain insights into these mechanisms. Irradiation of HLEC1 cells with 10% survival dose caused a growth delay but did not reduce viability. HLEC1 cells at high cumulative population doubling level were more susceptible to radiogenic premature senescence than WI-38 cells. Concerning p53 binding protein 1 (53BP1) foci, HLEC1 cells harbored less spontaneous foci but more radiogenic foci than in WI-38 cells, and the focus number returned to spontaneous levels within 48 h postirradiation both in HLEC1 and WI-38. The chemical inhibition of DNA repair kinases ataxia telangiectasia mutated, DNA-dependent protein kinase or both delayed and attenuated the appearance and disappearance of radiogenic 53BP1 foci, increased radiogenic premature senescence and enhanced clonogenic inactivation. The DNA microarray analysis suggested both radiogenic stimulation and inhibition of cell proliferation. Treatment with conditioned medium from irradiated cells did not change growth and the plating efficiency of nonirradiated cells. These results partially explain mechanisms of our previous observations, such that unrepaired or incompletely repaired DNA damage causes a growth delay in a subset of HLEC1 cells without changing viability through induction of premature senescence, thereby leading to clonogenic inactivation, but that growth is stimulated in another subset via as yet unidentified mechanisms, warranting further studies.

Dataset Information

Quantitative and qualitative mutational impact of ionizing radiation on normal cells.

Publications

Quantitative and qualitative mutational impact of ionizing radiation on normal cells.

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