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Irradiation induces DNA damage and modulates epigenetic effectors in distant bystander tissue in vivo

Oncogene volume 25, pages 4267–4275 (2006)Cite this article

Abstract

Irradiated cells induce chromosomal instability in unirradiated bystander cells in vitro. Although bystander effects are thought to be linked to radiation-induced secondary cancers, almost no studies have evaluated bystander effects in vivo. Furthermore, it has been proposed that epigenetic changes mediate bystander effects, but few studies have evaluated epigenetic factors in bystander tissues in vivo. Here, we describe studies in which mice were unilaterally exposed to X-irradiation and the levels of DNA damage, DNA methylation and protein expression were evaluated in irradiated and bystander cutaneous tissue. The data show that X-ray exposure to one side of the animal body induces DNA strand breaks and causes an increase in the levels of Rad51 in unexposed bystander tissue. In terms of epigenetic changes, unilateral radiation suppresses global methylation in directly irradiated tissue, but not in bystander tissue at given time-points studied. Intriguingly, however, we observed a significant reduction in the levels of the de novo DNA methyltransferases DNMT3a and 3b and a concurrent increase in the levels of the maintenance DNA methyltransferase DNMT1 in bystander tissues. Furthermore, the levels of two methyl-binding proteins known to be involved in transcriptional silencing, MeCP2 and MBD2, were also increased in bystander tissue. Together, these results show that irradiation induces DNA damage in bystander tissue more than a centimeter away from directly irradiated tissues, and suggests that epigenetic transcriptional regulation may be involved in the etiology of radiation-induced bystander effects.

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Acknowledgements

We thank James Meservy and Igor Kovalchuk for their critical reading of this manuscript. We are grateful to Katrin Boelsterli, Sandie Stevenson, Mike Baker and Anh Bui for their technical assistance and to Karen Dow-Cazal for animal care. This work was supported by the CIHR and NSERC operating grants to Olga Kovalchuk. We also acknowledge Dennis Fitzpatrick (Vice-President (Research) and Christopher Nicol (Dean of Art's and Science) of the University of Lethbridge for financial support. Jonathan Loree was a recipient of the NSERC Undergraduate Summer Research Award. Research in the Engelward laboratory was supported by the US National Institutes of Health (R33CA84740; R01CA79827; P01-CA26731; NIEHS P30 ES001209–26A1; P30-ES02109) and by the US Department of Energy (DE-FG01-04ER04).

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Authors and Affiliations

  1. Department of Biological Sciences, University of Lethbridge, Alberta, Canada

    I Koturbash, J Loree, B Thibault, K Kutanzi & O Kovalchuk

  2. Division of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA

    R E Rugo, C A Hendricks & B P Engelward

  3. Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR, USA

    I Pogribny

  4. Department of Nuclear Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA

    J C Yanch

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  1. I Koturbash
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Correspondence to O Kovalchuk.

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Koturbash, I., Rugo, R., Hendricks, C. et al. Irradiation induces DNA damage and modulates epigenetic effectors in distant bystander tissue in vivo. Oncogene 25, 4267–4275 (2006). https://doi.org/10.1038/sj.onc.1209467

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