Mutational impact and signature of ionizing radiation

Youk, Jeonghwan; Kwon, Hyun Woo; Lim, Joonoh; Kim, Eunji; Kim, Ryul; Park, Seongyeol; Yi, Kijong; Jeon, Sara; Choi, Jinwook; Na, Hyelin; Lee, Eunseok; Cho, Young-Won; Min, Dong-Wook; Kim, Hyojin; Kang, Yeong-Rok; Choi, Si Ho; Bae, Min Ji; Lee, Chang Geun; Kim, Joon-Goon; Kim, Young Seo; Lee, Dong Hoon; Kim, Tae You; Ku, Taeyun; Kim, Su Yeon; Koo, Bon‐Kyoung; Lee, Hyun‐Sook; Yi, On Vox; Han, Eon Chul; Chang, Ji Hyun; Kim, Kyung Soo; Son, Tae Gen; Ju, Young Seok

doi:10.1101/2021.01.12.426324

Cited by 3 publications

(7 citation statements)

References 25 publications

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“…A loss of this gene (whose full name is “X-Ray Repair Cross Complementing 4”) is well-appreciated to increase sensitivity to ionizing radiation 46–48 . Moreover, this indel signature is similar to the indel mutational signature provoked by ionizing hoton radiation, reported in a recent preprint, where clonal organoids from mouse and human cells were irradiated 49 .…”

Section: Resultssupporting

confidence: 79%

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Proton and alpha radiation-induced mutational profiles in human cells

Delhomme

Grilj

Biayna

et al. 2022

Preprint

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Ionizing radiation (IR) is known to be DNA damaging and mutagenic, however less is known about which mutational footprints result from exposures of human cells to different types of IR. We were interested in the mutagenic effects of particle radiation exposures on genomes of various human cell types, in order to gauge the genotoxic risks of space travel, and of certain types of tumor radiotherapy. To this end, we exposed cultured cell lines from the blood, breast and lung to intermittent proton and alpha particle (helium nuclei) beams at doses sufficient to affect cell survival. Whole-genome sequencing revealed that mutation rates were not overall markedly increased upon proton and alpha exposures. However, there were changes in mutation spectra and distributions, such as the increases in clustered mutations and of certain types of indels and structural variants. The spectrum of mutagenic effects of particle beams may often be cell-type and/or genetic background specific. Overall, the mutational effects of recurrent exposures to proton and alpha radiation on human cells appear subtle, however further work is warranted to understand effects of chronic, long-term exposures on various human tissues.

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Section: Resultssupporting

confidence: 79%

“…ID83D was found only in the MCF7 cell line and in both irradiated conditions, suggesting a possible tissue-specific mutagenic effect (it was not seen in blood or lung cells); this leaves similar footprints to those reported elsewhere for photon-based ionizing radiation 49 .…”

Section: Mutational Signatures Of Indels Across Cell Types and Condit...supporting

confidence: 84%

Proton and alpha radiation-induced mutational profiles in human cells

Delhomme

Grilj

Biayna

et al. 2022

Preprint

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“…ID83B was modeled as a mixture of 4 PCAWG signatures (Fig. 4 d), with higher weights of the ID12 (unknown aetiology) and ID8 (ionizing-radiation associated signature) 30 , 45 and ID4 (unknown aetiology). The spectrum of ID83B consists of various lengths (1–5 bp with similar frequency) insertions and deletions outside of DNA repeats, as well as a notable component of deletions with short flanking microhomology (mostly 1–2 nt; we note this contrasts with the microhomology-flanked deletions resulting from homologous recombination deficiencies, which tend to be ≥ 2 nt 46 ).…”

Section: Resultsmentioning

confidence: 99%

Proton and alpha radiation-induced mutational profiles in human cells

Delhomme

Munteanu

Grilj

et al. 2023

Sci Rep

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Ionizing radiation is known to be DNA damaging and mutagenic, however less is known about which mutational footprints result from exposures of human cells to different types of radiation. We were interested in the mutagenic effects of particle radiation exposures on genomes of various human cell types, in order to gauge the genotoxic risks of galactic cosmic radiation, and of certain types of tumor radiotherapy. To this end, we exposed cultured cell lines from the human blood, breast and lung to fractionated proton and alpha particle (helium nuclei) beams at doses sufficient to considerably affect cell viability. Whole-genome sequencing revealed that mutation rates were not overall markedly increased upon proton and alpha exposures. However, there were modest changes in mutation spectra and distributions, such as the increases in clustered mutations and of certain types of indels and structural variants. The spectrum of mutagenic effects of particle beams may be cell-type and/or genetic background specific. Overall, the mutational effects of repeated exposures to proton and alpha radiation on human cells in culture appear subtle, however further work is warranted to understand effects of long-term exposures on various human tissues.

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“…The highest proportion of mutants being SNVs is in line with the analysis of IR induced secondary tumours [ 17 ]. In contrast, increased SNVs could not be detected in thyroid carcinomas, linked to the Chernobyl disaster [ 19 ] and irradiated human organoids [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

“…More recent studies, analysing thyroid carcinomas, linked to Iodine-131 exposure related to the Chernobyl disaster failed to detect increased SNV levels, indels and SVs being increased [ 19 ]. Human organoid exposure to IR similarly only led to increased indels and SVs [ 20 ]. In radiation induced tumours induced in p53 mutant mice SNVs levels were reported to be rare, indels and SV being detectable [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

C. elegans genome-wide analysis reveals DNA repair pathways that act cooperatively to preserve genome integrity upon ionizing radiation

et al. 2021

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Ionizing radiation (IR) is widely used in cancer therapy and accidental or environmental exposure is a major concern. However, little is known about the genome-wide effects IR exerts on germ cells and the relative contribution of DNA repair pathways for mending IR-induced lesions. Here, using C. elegans as a model system and using primary sequencing data from our recent high-level overview of the mutagenic consequences of 11 genotoxic agents, we investigate in detail the genome-wide mutagenic consequences of exposing wild-type and 43 DNA repair and damage response defective C. elegans strains to a Caesium (Cs-137) source, emitting γ-rays. Cs-137 radiation induced single nucleotide variants (SNVs) at a rate of ~1 base substitution per 3 Gy, affecting all nucleotides equally. In nucleotide excision repair mutants, this frequency increased 2-fold concurrently with increased dinucleotide substitutions. As observed for DNA damage induced by bulky DNA adducts, small deletions were increased in translesion polymerase mutants, while base changes decreased. Structural variants (SVs) were augmented with dose, but did not arise with significantly higher frequency in any DNA repair mutants tested. Moreover, 6% of all mutations occurred in clusters, but clustering was not significantly altered in any DNA repair mutant background. Our data is relevant for better understanding how DNA repair pathways modulate IR-induced lesions.

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Mutational impact and signature of ionizing radiation

Cited by 3 publications

References 25 publications

Proton and alpha radiation-induced mutational profiles in human cells

Proton and alpha radiation-induced mutational profiles in human cells

Proton and alpha radiation-induced mutational profiles in human cells

C. elegans genome-wide analysis reveals DNA repair pathways that act cooperatively to preserve genome integrity upon ionizing radiation

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