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Radiation-Induced Delayed Genome Instability and Hypermutation in Mammalian Cells

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Stress-Induced Mutagenesis

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Abstract

Genome instability is a hallmark of cancer cells. Inherited cancer predisposition syndromes typically show defects in DNA repair or DNA damage checkpoint systems, collectively called the DNA damage response (DDR). Several mutations in key genes are required to convert a normal cell to a cancer cell, suggesting that an early step in carcinogenesis is the acquisition of a “genome instability” (mutator) phenotype. DDR proteins suppress cancer by preventing spontaneous damage from causing excessive genome instability, and thus, normal cells display very low mutation rates and stable genomes. Genotoxins such as DNA-reactive chemicals and radiation cause DNA damage that results in small- and large-scale genetic change (mutations). Recently it has become clear that radiation, including ionizing radiation (IR) such X-rays and charged particles (heavy ion radiation), as well as nonionizing radiation (UV light) induce genome instability many cell generations after the exposure. These delayed effects are seen after high (1–10 Gy) and very low (0.01–0.1 Gy) IR doses, and include hypermutation, hyper-homologous recombination, chromosome instability, and reduced clonogenic survival (delayed death). Similar to immediate effects of radiation, delayed effects show adaptive responses. Here we focus on potential mechanisms that underlie radiation-induced delayed genome instabilities, and discuss the risks of genome destabilizing effects of occupational and accidental radiation exposures, and clinical exposures associated with radiation therapy and diagnostic imaging procedures.

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Acknowledgments

We thank Joel Bedford, Howard Liber, Susan Bailey, Michael Weil, and William Morgan for many helpful discussions. Research in the Nickoloff laboratory is supported by NIH grant R01 GM084020, and by the Japan National Institute of Radiological Sciences (NIRS) International Open Laboratory program. Research in the Okayasu and Fujimori laboratories is supported by the NIRS, and Okayasu also receives support from a Grant-in-Aid award from the Japan Society for the Promotion of Science.

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  1. Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, 80523, USA

    Christopher P. Allen & Jac A. Nickoloff

  2. Research Center for Charged Particle Therapy, and International Open Laboratory, National Institute of Radiological Sciences, 263-8555, Chiba, Japan

    Christopher P. Allen, Akira Fujimori & Ryuichi Okayasu

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  1. Christopher P. Allen
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  2. Akira Fujimori
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Correspondence to Jac A. Nickoloff .

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    David Mittelman

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Allen, C.P., Fujimori, A., Okayasu, R., Nickoloff, J.A. (2013). Radiation-Induced Delayed Genome Instability and Hypermutation in Mammalian Cells. In: Mittelman, D. (eds) Stress-Induced Mutagenesis. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-6280-4_9

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