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      Exposure to galactic cosmic radiation compromises DNA repair and increases the potential for oncogenic chromosomal rearrangement in bronchial epithelial cells

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          Abstract

          Participants in deep space missions face protracted exposure to galactic cosmic radiation (GCR). In this setting, lung cancer is a significant component of the overall risk of radiation-exposure induced death. Here we investigate persistent effects of GCR exposure on DNA repair capacity in lung-derived epithelial cells, using an enzyme-stimulated chromosomal rearrangement as an endpoint. Replicate cell cultures were irradiated with energetic 48Ti ions (a GCR component) or reference γ-rays. After a six-day recovery, they were challenged by expression of a Cas9/sgRNA pair that creates double-strand breaks simultaneously in the EML4 and ALK loci, misjoining of which creates an EML4-ALK fusion oncogene. Misjoining was significantly elevated in 48Ti-irradiated populations, relative to the baseline rate in mock-irradiated controls. The effect was not seen in γ-ray irradiated populations exposed to equal or higher radiation doses. Sequence analysis of the EML4-ALK joints from 48Ti-irradiated cultures showed that they were far more likely to contain deletions, sometimes flanked by short microhomologies, than equivalent samples from mock-irradiated cultures, consistent with a shift toward error-prone alternative nonhomologous end joining repair. Results suggest a potential mechanism by which a persistent physiological effect of GCR exposure may increase lung cancer risk.

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          Most cited references 49

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          Immortalization of human bronchial epithelial cells in the absence of viral oncoproteins.

          By expressing two genes (hTERT and Cdk4), we have developed a method to reproducibly generate continuously replicating human bronchial epithelial cell (HBEC) lines that provide a novel resource to study the molecular pathogenesis of lung cancer and the differentiation of bronchial epithelial cells. Twelve human bronchial epithelial biopsy specimens obtained from persons with and without lung cancer were placed into short-term culture and serially transfected with retroviral constructs containing cyclin-dependent kinase (Cdk) 4 and human telomerase reverse transcriptase (hTERT), resulting in continuously growing cultures. The order of introduction of Cdk4 and hTERT did not appear to be important; however, transfection of either gene alone did not result in immortalization. Although they could be cloned, the immortalized bronchial cells did not form colonies in soft agar or tumors in nude mice. The immortalized HBECs have epithelial morphology; express epithelial markers cytokeratins 7, 14, 17, and 19, the stem cell marker p63, and high levels of p16(INK4a); and have an intact p53 checkpoint pathway. Cytogenetic analysis and array comparative genomic hybridization profiling show immortalized HBECs to have duplication of parts of chromosomes 5 and 20. Microarray gene expression profiling demonstrates that the Cdk4/hTERT-immortalized bronchial cell lines clustered together and with nonimmortalized bronchial cells, distinct from lung cancer cell lines. We also immortalized several parental cultures with viral oncoproteins human papilloma virus type 16 E6/E7 with and without hTERT, and these cells exhibited loss of the p53 checkpoint and significantly different gene expression profiles compared with Cdk4/hTERT-immortalized HBECs. These HBEC lines are a valuable new tool for studying of the pathogenesis of lung cancer.
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            Modernizing the nonhomologous end-joining repertoire: alternative and classical NHEJ share the stage.

            DNA double-strand breaks (DSBs) are common lesions that continually threaten genomic integrity. Failure to repair a DSB has deleterious consequences, including cell death. Misrepair is also fraught with danger, especially inappropriate end-joining events, which commonly underlie oncogenic transformation and can scramble the genome. Canonically, cells employ two basic mechanisms to repair DSBs: homologous recombination (HR) and the classical nonhomologous end-joining pathway (cNHEJ). More recent experiments identified a highly error-prone NHEJ pathway, termed alternative NHEJ (aNHEJ), which operates in both cNHEJ-proficient and cNHEJ-deficient cells. aNHEJ is now recognized to catalyze many genome rearrangements, some leading to oncogenic transformation. Here, we review the mechanisms of cNHEJ and aNHEJ, their interconnections with the DNA damage response (DDR), and the mechanisms used to determine which of the three DSB repair pathways is used to heal a particular DSB. We briefly review recent clinical applications involving NHEJ and NHEJ inhibitors.
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              Mars' surface radiation environment measured with the Mars Science Laboratory's Curiosity rover.

              The Radiation Assessment Detector (RAD) on the Mars Science Laboratory's Curiosity rover began making detailed measurements of the cosmic ray and energetic particle radiation environment on the surface of Mars on 7 August 2012. We report and discuss measurements of the absorbed dose and dose equivalent from galactic cosmic rays and solar energetic particles on the martian surface for ~300 days of observations during the current solar maximum. These measurements provide insight into the radiation hazards associated with a human mission to the surface of Mars and provide an anchor point with which to model the subsurface radiation environment, with implications for microbial survival times of any possible extant or past life, as well as for the preservation of potential organic biosignatures of the ancient martian environment.
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                Author and article information

                Contributors
                wdynan@emory.edu
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                23 July 2018
                23 July 2018
                2018
                : 8
                Affiliations
                [1 ]ISNI 0000 0001 0941 6502, GRID grid.189967.8, Department of Radiation Oncology, , Emory University School of Medicine, ; 1365 Clifton Rd NE, Atlanta, GA 30322 USA
                [2 ]ISNI 0000 0001 0941 6502, GRID grid.189967.8, Department of Biochemistry, , Emory University School of Medicine, ; 1510 Clifton Rd NE, Atlanta, GA 30322 USA
                [3 ]ISNI 0000 0001 0941 6502, GRID grid.189967.8, Winship Cancer Institute, , Emory University School of Medicine, ; 1365 Clifton Rd NE, Atlanta, GA 30322 USA
                [4 ]ISNI 0000 0000 9482 7121, GRID grid.267313.2, Department of Radiation Oncology, , University of Texas Southwestern Medical Center, ; 6000 Harry Hines Blvd, Dallas, TX 75390 USA
                [5 ]ISNI 0000 0004 0456 3986, GRID grid.262103.4, Department of Physics, Radiation Institute for Science and Engineering (RaISE), , 100 University Dr, Prairie View A&M University, ; Prairie View, TX 77446 USA
                Article
                29350
                10.1038/s41598-018-29350-5
                6056477
                30038404
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                Funding
                Funded by: FundRef https://doi.org/10.13039/100000104, National Aeronautics and Space Administration (NASA);
                Award ID: NNX15AD63G
                Award ID: NNX11AC30G
                Award ID: NNX11AC54G
                Award ID: NNX15AD63G
                Award ID: NNX11AC30G
                Award ID: NNX11AC54G
                Award ID: NNX15AD63G
                Award ID: NNX11AC30G
                Award ID: NNX11AC54G
                Award ID: NNX15AD63G
                Award ID: NNX11AC30G
                Award ID: NNX11AC54G
                Award ID: NNX15AD63G
                Award ID: NNX11AC30G
                Award ID: NNX11AC54G
                Award ID: NNX15AD63G
                Award ID: NNX11AC30G
                Award ID: NNX11AC54G
                Award ID: NNX11AC30G
                Award ID: NNX11AC54G
                Award ID: NNX15AD63G
                Award ID: NNX11AC30G
                Award ID: NNX15AD63G
                Award ID: NNX11AC30G
                Award ID: NNX11AC54G
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