Acute High-Dose X-Radiation-Induced Genomic Changes in A549 Cells

Abstract

Accidents with ionizing radiation often involve single, acute high-dose exposures that can lead to acute radiation syndrome and late effects such as carcinogenesis. To study such effects at the cellular level, we investigated acute ionizing radiation-induced chromosomal aberrations in A549 adenocarcinoma cells at the genome-wide level by exposing the cells to an acute dose of 6 Gy 240 kV X rays. One sham-irradiated clone and four surviving irradiated clones were recovered by minimal dilution and further expanded and analyzed by chromosome painting and tiling-path array CGH, with the nonirradiated clone 0 serving as the control. Acute X-ray exposure induced specific translocations and changes in modal chromosome number in the four irradiated clones. Array CGH disclosed unique and recurrent genomic changes, predominantly losses, and revealed that the fragile sites FRA3B and FRA16D were preferential regions of genomic alterations in all irradiated clones, which is likely related to radioresistant S-phase progression and genomic stress. Furthermore, clone 4 displayed an increased radiosensitivity at doses >5 Gy. Pairwise comparisons of the gene expression patterns of all irradiated clones to the sham-irradiated clone 0 revealed an enrichment of the Gene Ontology term "M Phase" (P = 6.2 × 10(-7)) in the set of differentially expressed genes of clone 4 but not in those of clones 1-3. Ionizing radiation-induced genomic changes and fragile site expression highlight the capacity of a single acute radiation exposure to affect the genome of exposed cells by inflicting genomic stress.

Transcriptome Alterations In X-Irradiated Human Gingiva Fibroblasts

“…Fusion transcripts from cis are likely the result of intrachromosomal deletions/fusions, which by molecular cytogenetic methods go largely undetected. A prevalence of fusion transcripts from deletions in this investigation goes along with the notion that high dose/dose rate exposures lead predominantly to genomic losses ( Finn et al 2004 ; Muradyan et al 2011 ). Moreover, the protein coding part, which is the subject of this investigation, comprises only about 2% of the human genome.…”

Common fragile site instability in normal cells: Lessons and perspectives

“…Interestingly, three CNVs, affecting directly or indirectly the FHIT gene, were detected in clones showing karyotypic instability. At the same time, the majority of cell clones derived from irradiated cells did not exhibit genomic alterations at FHIT , although FRA3B is a well‐known hot spot for radiation‐induced fragility . These results can be interpreted in light of the physiological protective function of FHIT against IR‐induced DNA damage and its role of genome stability caretaker …”

“…At the same time, the majority of cell clones derived from irradiated cells did not exhibit genomic alterations at FHIT, 85 although FRA3B is a well-known hot spot for radiation-induced fragility. 86,87 These results can be interpreted in light of the physiological protective function of FHIT against IR-induced DNA damage and its role of genome stability caretaker. 75,76 Thus, intricate networks justify the relationship between CFS instability and CNVs, 35 and studies using nontumor cells have contributed to shed light in this puzzle and to identify new pathways acting in the DDR.…”

Analysis of copy number variations induced by ultrashort electron beam radiation in human leukocytes in vitro

“…Several previous studies described radiation-induced CNVs in TK6 cells, a human B-cell lymphoblastoid cell line of nonmalignant origin after gamma irradiations with the prevalence of gains [52], and in aneuploid A549 male non-small cell lung cancer adenocarcinoma cell line irradiated with X rays [53]. Increase of CNVs was shown in mouse thymic lymphomas induced by gamma-irradiation in vivo [54].…”