Autosomal mutants of proton-exposed kidney cells display frequent loss of heterozygosity on nonselected chromosomes

Dmytro Grygoryev, Cristian Dan, Stacey Gauny, Bradley Eckelmann, Anna P. Ohlrich, Marissa Connolly, Michael Lasarev, Gianfranco Grossi, Amy Kronenberg, Mitchell Turker

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

High-energy protons found in the space environment can induce mutations and cancer, which are inextricably linked. We hypothesized that some mutants isolated from proton-exposed kidneys arose through a genome-wide incident that causes loss of heterozygosity (LOH)-generating mutations on multiple chromosomes (termed here genomic LOH). To test this hypothesis, we examined 11 pairs of nonselected chromosomes for LOH events in mutant cells isolated from the kidneys of mice exposed to 4 or 5 Gy of 1 GeV protons. The mutant kidney cells were selected for loss of expression of the chromosome 8-encoded Aprt gene. Genomic LOH events were also assessed in Aprt mutants isolated from isogenic cultured kidney epithelial cells exposed to 5 Gy of protons in vitro. Control groups were spontaneous Aprt mutants and clones isolated without selection from the proton-exposed kidneys or cultures. The in vivo results showed significant increases in genomic LOH events in the Aprt mutants from proton-exposed kidneys when compared with spontaneous Aprt mutants and when compared with nonmutant (i.e., nonselected) clones from the proton-exposed kidneys. A bias for LOH events affecting chromosome 14 was observed in the proton-induced Aprt mutants, though LOH for this chromosome did not confer increased radiation resistance. Genomic LOH events were observed in Aprt mutants isolated from proton-exposed cultured kidney cells; however the incidence was fivefold lower than in Aprt mutants isolated from exposed intact kidneys, suggesting a more permissive environment in the intact organ and/or the evolution of kidney clones prior to their isolation from the tissue. We conclude that proton exposure creates a subset of viable cells with LOH events on multiple chromosomes, that these cells form and persist in vivo, and that they can be isolated from an intact tissue by selection for a mutation on a single chromosome.

Original languageEnglish (US)
Pages (from-to)452-463
Number of pages12
JournalRadiation Research
Volume181
Issue number5
DOIs
StatePublished - 2014

Fingerprint

Loss of Heterozygosity
chromosomes
kidneys
Protons
Chromosomes
Kidney
protons
cells
mutations
Clone Cells
Mutation
Chromosomes, Human, Pair 14
Chromosomes, Human, Pair 8
genome
aerospace environments
radiation tolerance
proton energy
organs
genes
set theory

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging
  • Biophysics
  • Radiation

Cite this

Autosomal mutants of proton-exposed kidney cells display frequent loss of heterozygosity on nonselected chromosomes. / Grygoryev, Dmytro; Dan, Cristian; Gauny, Stacey; Eckelmann, Bradley; Ohlrich, Anna P.; Connolly, Marissa; Lasarev, Michael; Grossi, Gianfranco; Kronenberg, Amy; Turker, Mitchell.

In: Radiation Research, Vol. 181, No. 5, 2014, p. 452-463.

Research output: Contribution to journalArticle

Grygoryev, D, Dan, C, Gauny, S, Eckelmann, B, Ohlrich, AP, Connolly, M, Lasarev, M, Grossi, G, Kronenberg, A & Turker, M 2014, 'Autosomal mutants of proton-exposed kidney cells display frequent loss of heterozygosity on nonselected chromosomes', Radiation Research, vol. 181, no. 5, pp. 452-463. https://doi.org/10.1667/RR13654.1
Grygoryev, Dmytro ; Dan, Cristian ; Gauny, Stacey ; Eckelmann, Bradley ; Ohlrich, Anna P. ; Connolly, Marissa ; Lasarev, Michael ; Grossi, Gianfranco ; Kronenberg, Amy ; Turker, Mitchell. / Autosomal mutants of proton-exposed kidney cells display frequent loss of heterozygosity on nonselected chromosomes. In: Radiation Research. 2014 ; Vol. 181, No. 5. pp. 452-463.
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AU - Dan, Cristian

AU - Gauny, Stacey

AU - Eckelmann, Bradley

AU - Ohlrich, Anna P.

AU - Connolly, Marissa

AU - Lasarev, Michael

AU - Grossi, Gianfranco

AU - Kronenberg, Amy

AU - Turker, Mitchell

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