Ionizing Radiation Induces Delayed Hyperrecombination in Mammalian Cells

Huang, Lei; Grim, Suzanne; Smith, Leslie E.; Kim, Perry M.; Nickoloff, Jac A.; Goloubeva, Olga; Morgan, William F.

doi:10.1128/mcb.24.11.5060-5068.2004

Cited by 40 publications

(50 citation statements)

References 44 publications

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“…When growth medium is transferred from these unstable cells to the parent GM10115 cells, it is cytotoxic (16). We previously isolated seven chromosomally unstable derivatives of RKO36 that survived 10-Gy X-irradiation (23) and these are distinct from the unstable RKO36 derivatives that display delayed genomic instability as measured by GFP +/À colonies. We were interested in whether the chromosomally unstable RKO36 cells show a similar death-inducing effect as with GM10115 cells.…”

Section: Resultsmentioning

confidence: 99%

“…Genomic instability was evaluated in RKO36 cells by analysis of homologous recombination and mutation/deletion at the GFP direct repeat substrate and measured as the number of GFP ). Genomic instability, as measured by this GFP-based assay, is defined by colonies with both GFP + and GFP À cells, with >10 cells of each type in a colony (23,26). The frequency of induced instability was calculated as the number of GFP +/À colonies per total surviving colonies scored.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…RKO36 cells are derivatives of RKO human colorectal carcinoma cells carrying a green fluorescent protein (GFP) direct repeat homologous recombination substrate (23). One copy of GFP is driven by the cytomegalovirus promoter but is inactivated by an XhoI linker frameshift mutation, and the second copy has wild-type coding capacity but is inactive because it lacks a promoter (23). GM10115 cells are human-hamster hybrid cells, and LS12 and Fe-10-3 cells are chromosomally unstable cell clones of GM10115 cells derived from single cells surviving exposure to ionizing radiation (24,25).…”

Section: Methodsmentioning

confidence: 99%

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Targeted and Nontargeted Effects of Low-Dose Ionizing Radiation on Delayed Genomic Instability in Human Cells

Huang

Kim²,

Nickoloff³

et al. 2007

Cancer Research

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All humans receive some radiation exposure and the risk for radiation-induced cancer at low doses is based on the assumption that there is a linear non-threshold relationship between dose and subsequent effect. Consequently, risk is extrapolated linearly from high radiation doses to very low doses. However, adaptive responses, bystander effects, and death-inducing effect may influence health effects associated with low-dose radiation exposure. Adaptive response is the phenomenon by which cells irradiated with a sublethal radiation dose can become less susceptible to subsequent high-dose radiation exposure. Bystander effects are nontargeted effects observed in cells that were not irradiated but were either in contact with or received soluble signals from irradiated cells. These non-hit bystander cells can exhibit damage typically associated with direct radiation exposure. Death-inducing effect is a phenomenon whereby medium from human-hamster hybrid cells displaying radiation-induced chromosomal instability is toxic to unirradiated parental cells. In this study, we show that human RKO cells do not exhibit adaptive response, bystander effect, or death-inducing effect, as measured by cell killing, or delayed genomic instability in a stably transfected plasmidbased green fluorescent protein assay measuring homologous recombination and delayed mutation/deletion events. However, growth medium conditioned by some chromosomally unstable RKO derivatives induced genomic instability, indicating that these cells can secrete factor(s) that elicit responses in nonirradiated cells. Furthermore, low radiation doses suppressed the induction of delayed genomic instability by a subsequent high dose, indicative of an adaptive response for radiation-induced genomic instability. These results highlight the inherent variability in cellular responses to low-dose radiation exposure and add to the uncertainties associated with evaluating potential hazards at these low doses. [Cancer Res 2007;67(3):1099-104]

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Targeted and Nontargeted Effects of Low-Dose Ionizing Radiation on Delayed Genomic Instability in Human Cells

Huang

Kim²,

Nickoloff³

et al. 2007

Cancer Research

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“…Concurrent with the preparation of this manuscript, Huang et al (2004) showed that ionizing radiation induces delayed hyper-recombination in mammalian cells. Here, we have shown the following: (1) persistent hyper-recombination is not confined to ionizing radiation (more than 30 cell doublings after exposure to MMC, mammalian cells suffer an increased risk of recombination); (2) chemically induced hyperrecombination is not due to residual damage or inherited mutations; (3) unexposed naive cells can become hyper-rec merely by coculture with either cells descended from exposed populations or naı¨ve cells cocultured with such descendants.…”

Section: Introductionmentioning

confidence: 99%

A single acute exposure to a chemotherapeutic agent induces hyper-recombination in distantly descendant cells and in their neighbors

et al. 2005

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Homologous recombination can induce tumorigenic sequence rearrangements. Here, we show that persistent hyper-recombination can be induced following exposure to a bifunctional alkylating agent, mitomycin C (MMC), and that the progeny of exposed cells induce a hyperrecombination phenotype in unexposed neighboring cells. Residual damage cannot be the cause of delayed recombination events, since recombination is observed after drug and template damage are diluted over a millionfold. Furthermore, not only do progeny of MMC-exposed cells induce recombination in unexposed cells (bystanders), but these bystanders can in turn induce recombination in their unexposed neighbors. Thus, a signal to induce homologous recombination can be passed from cell to cell. Although the underlying molecular mechanism is not yet known, these studies reveal that cells suffer consequences of damage long after exposure, and that can signal unexposed neighboring cells to respond similarly. Thus, a single acute exposure to a chemotherapeutic agent can cause long-term changes in genomic stability. If the results of these studies of mouse embryonic stem (ES) cells are generally applicable to many cell types, these results suggest that a relatively small number of cells could potentially induce a tissue-wide increase in the risk of de novo homologous recombination events.

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Radiation-Induced Delayed Genome Instability and Hypermutation in Mammalian Cells

Allen

Fujimori

Okayasu

et al. 2013

Stress-Induced Mutagenesis

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Ionizing Radiation Induces Delayed Hyperrecombination in Mammalian Cells

Cited by 40 publications

References 44 publications

Targeted and Nontargeted Effects of Low-Dose Ionizing Radiation on Delayed Genomic Instability in Human Cells

Targeted and Nontargeted Effects of Low-Dose Ionizing Radiation on Delayed Genomic Instability in Human Cells

A single acute exposure to a chemotherapeutic agent induces hyper-recombination in distantly descendant cells and in their neighbors

Radiation-Induced Delayed Genome Instability and Hypermutation in Mammalian Cells

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