Autosomal mutations in mouse kidney epithelial cells exposed to high-energy protons in vivo or in culture

Mitchell Turker, Dmytro Grygoryev, Cristian Dan, Bradley Eckelmann, Michael Lasarev, Stacey Gauny, Ely Kwoh, Amy Kronenberg

Research output: Contribution to journalArticle

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Abstract

Proton exposure induces mutations and cancer, which are presumably linked. Because protons are abundant in the space environment and significant uncertainties exist for the effects of space travel on human health, the purpose of this study was to identify the types of mutations induced by exposure of mammalian cells to 4-5 Gy of 1 GeV protons. We used an assay that selects for mutations affecting the chromosome 8-encoded Aprt locus in mouse kidney cells and selected mutants after proton exposure both in vivo and in cell culture. A loss of heterozygosity (LOH) assay for DNA preparations from the in vivo-derived kidney mutants revealed that protons readily induced large mutational events. Fluorescent in situ hybridization painting for chromosome 8 showed that >70% of proton-induced LOH patterns resembling mitotic recombination were in fact the result of nonreciprocal chromosome translocations, thereby demonstrating an important role for DNA double-strand breaks in proton mutagenesis. Large interstitial deletions, which also require the formation and resolution of double-strand breaks, were significantly induced in the cell culture environment (14% of all mutants), but to a lesser extend in vivo (2% of all mutants) suggesting that the resolution of proton-induced double-strand breaks can differ between the intact tissue and cell culture microenvironments. In total, the results demonstrate that double-strand break formation is a primary determinant for proton mutagenesis in epithelial cell types and suggest that resultant LOH for significant genomic regions play a critical role in proton-induced cancers.

Original languageEnglish (US)
Pages (from-to)521-529
Number of pages9
JournalRadiation Research
Volume179
Issue number5
DOIs
StatePublished - May 2013

Fingerprint

kidneys
mutations
proton energy
mice
Protons
Epithelial Cells
Kidney
Mutation
protons
strands
Loss of Heterozygosity
chromosomes
mutagenesis
Chromosomes, Human, Pair 8
Cell Culture Techniques
Mutagenesis
deoxyribonucleic acid
cancer
Cellular Microenvironment
deletion

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging
  • Biophysics
  • Radiation

Cite this

Turker, M., Grygoryev, D., Dan, C., Eckelmann, B., Lasarev, M., Gauny, S., ... Kronenberg, A. (2013). Autosomal mutations in mouse kidney epithelial cells exposed to high-energy protons in vivo or in culture. Radiation Research, 179(5), 521-529. https://doi.org/10.1667/RR3174.1

Autosomal mutations in mouse kidney epithelial cells exposed to high-energy protons in vivo or in culture. / Turker, Mitchell; Grygoryev, Dmytro; Dan, Cristian; Eckelmann, Bradley; Lasarev, Michael; Gauny, Stacey; Kwoh, Ely; Kronenberg, Amy.

In: Radiation Research, Vol. 179, No. 5, 05.2013, p. 521-529.

Research output: Contribution to journalArticle

Turker, M, Grygoryev, D, Dan, C, Eckelmann, B, Lasarev, M, Gauny, S, Kwoh, E & Kronenberg, A 2013, 'Autosomal mutations in mouse kidney epithelial cells exposed to high-energy protons in vivo or in culture', Radiation Research, vol. 179, no. 5, pp. 521-529. https://doi.org/10.1667/RR3174.1
Turker, Mitchell ; Grygoryev, Dmytro ; Dan, Cristian ; Eckelmann, Bradley ; Lasarev, Michael ; Gauny, Stacey ; Kwoh, Ely ; Kronenberg, Amy. / Autosomal mutations in mouse kidney epithelial cells exposed to high-energy protons in vivo or in culture. In: Radiation Research. 2013 ; Vol. 179, No. 5. pp. 521-529.
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