Genetic and epigenetic profile changes associated with individual radiation sensitivity are well documented and have led to enhanced understanding of the mechanisms of the radiation-induced DNA damage response. However, the search continues to identify reliable biomarkers of individual radiation sensitivity. Herein, we report on a multi-biomarker approach using traditional cytogenetic biomarkers, DNA damage biomarkers and transcriptional microRNA (miR) biomarkers coupled with their potential gene targets to identify radiosensitivity in ataxia-telangiectasia mutated (ATM)-deficient lymphoblastoid cell lines (LCL); ATM-proficient cell lines were used as controls. Cells were 0.05 and 0.5 Gy irradiated, using a linear accelerator, with sham-irradiated cells as controls. At 1 h postirradiation, cells were fixed for γ-H2AX analysis as a measurement of DNA damage, and cytogenetic analysis using the G2 chromosomal sensitivity assay, G-banding and FISH techniques. RNA was also isolated for genetic profiling by microRNA (miR) and RT-PCR analysis. A panel of 752 miR were analyzed, and potential target genes, phosphatase and tensin homolog (PTEN) and cyclin D1 (CCND1), were measured. The cytogenetic assays revealed that although the control cell line had functional cell cycle checkpoints, the radiosensitivity of the control and AT cell lines were similar. Analysis of DNA damage in all cell lines, including an additional control cell line, showed elevated γ-H2AX levels for only one AT cell line. Of the 752 miR analyzed, eight miR were upregulated, and six miR were downregulated in the AT cells compared to the control. Upregulated miR-152-3p, miR-24-5p and miR-92-15p and all downregulated miR were indicated as modulators of PTEN and CCDN1. Further measurement of both genes validated their potential role as radiation-response biomarkers. The multi-biomarker approach not only revealed potential candidates for radiation response, but provided additional mechanistic insights into the response in AT-deficient cells.
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June 2020
Research Article|
March 27 2020
MicroRNA Analysis of ATM-Deficient Cells Indicate PTEN and CCDN1 as Potential Biomarkers of Radiation Response
Jane Bryant;
Jane Bryant
Radiation and Environmental Science Centre (RESC), FOCAS Research Institute
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Lisa White;
Lisa White
Radiation and Environmental Science Centre (RESC), FOCAS Research Institute
School of Biological and Health Sciences, Technological University Dublin, City Campus, Dublin 8, Ireland
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Natasha Coen;
Natasha Coen
Department of Clinical Genetics, Division of Cytogenetics, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland
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Laura Shields;
Laura Shields
Medical Physics Department, St Luke's Radiation Oncology Centre, Rathgar, Dublin 6, Ireland
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Brendan McClean;
Brendan McClean
Medical Physics Department, St Luke's Radiation Oncology Centre, Rathgar, Dublin 6, Ireland
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Aidan D. Meade;
Aidan D. Meade
Radiation and Environmental Science Centre (RESC), FOCAS Research Institute
School of Physics & Clinical & Optometric Sciences, Technological University Dublin, City Campus, Dublin 8, Ireland
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Fiona M. Lyng;
Fiona M. Lyng
Radiation and Environmental Science Centre (RESC), FOCAS Research Institute
School of Physics & Clinical & Optometric Sciences, Technological University Dublin, City Campus, Dublin 8, Ireland
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Orla Howe
Orla Howe
1
Radiation and Environmental Science Centre (RESC), FOCAS Research Institute
School of Biological and Health Sciences, Technological University Dublin, City Campus, Dublin 8, Ireland
1 Address for correspondence: Rm G-029, School of Biological & Health Sciences, Technological University Dublin, City Campus, Kevin St, Dublin 8, Ireland; email: orla.howe@TUDublin.ie.
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Radiat Res (2020) 193 (6): 520–530.
Article history
Received:
June 26 2019
Accepted:
March 06 2020
Citation
Jane Bryant, Lisa White, Natasha Coen, Laura Shields, Brendan McClean, Aidan D. Meade, Fiona M. Lyng, Orla Howe; MicroRNA Analysis of ATM-Deficient Cells Indicate PTEN and CCDN1 as Potential Biomarkers of Radiation Response. Radiat Res 1 June 2020; 193 (6): 520–530. doi: https://doi.org/10.1667/RR15462.1
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