Abstract
Mutation induction in directly exposed cells is currently regarded as the main component of the genetic risk of ionizing radiation for humans. However, recent data on the transgenerational increases in mutation rates in the offspring of irradiated parents indicate that the genetic risk could be greater than predicted previously. Here, we have analysed transgenerational changes in mutation rates and DNA damage in the germline and somatic tissues of non-exposed first-generation offspring of irradiated inbred male CBA/Ca and BALB/c mice. Mutation rates at an expanded simple tandem repeat DNA locus and a protein-coding gene (hprt) were significantly elevated in both the germline (sperm) and somatic tissues of all the offspring of irradiated males. The transgenerational changes in mutation rates were attributed to the presence of a persistent subset of endogenous DNA lesions (double- and single-strand breaks), measured by the phosphorylated form of histone H2AX (γ-H2AX) and alkaline Comet assays. Such remarkable transgenerational destabilization of the F1 genome may have important implications for cancer aetiology and genetic risk estimates. Our data also provide important clues on the still unknown mechanisms of radiation-induced genomic instability.
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References
Almeida GM, Duarte TL, Steward WP, Jones GDD . (2006). DNA Repair 5: 219–225.
Anway MD, Cupp AS, Uzumcu M, Skinner MK . (2005). Science 308: 1466–1469.
Bakkenist CJ, Kastan MB . (2004). Cell 118: 9–17.
Barber R, Plumb MA, Boulton E, Roux I, Dubrova YE . (2002). Proc Natl Acad Sci USA 99: 6877–6882.
Barber RC, Miccoli L, van Buul PPW, Burr KL-A, van Duyn-Goedhart A, Angulo JF et al. (2004). Mutat Res 554: 287–295.
Bartkova J, Horejsi Z, Koed K, Kramer A, Tort F, Zieger K et al. (2005). Nature 434: 864–870.
Bol SA, van Steeg H, Jansen JG, Van Oostrom C, de Vries A, de Groot AJ et al. (1998). Cancer Res 58: 2850–2856.
Breger KS, Smith L, Turker MS, Thayer M . (2004). Cancer Res 64: 8231–8238.
Collins AR, Dusinska M . (2002). Methods Mol Biol 186: 147–159.
Cosentino L, Heddle JA . (2000). Mutat Res 454: 1–10.
Dubrova YE . (2003). Oncogene 22: 7087–7093.
Dubrova YE . (2005). Radiat Res 163: 200–207.
Dubrova YE, Plumb M, Gutierrez B, Boulton E, Jeffreys AJ . (2000). Nature 405: 37.
Friedberg EC, Walker GC, Siede W . (1995). DNA Repair and Mutagenesis. ASM Press: Washington, DC.
Furth EE, Thilly WG, Penman BW, Liber HL, Rand WM . (1981). Anal Biochem 110: 1–8.
Gorgoulis VG, Vassiliou LV, Karakaidos P, Zacharatos P, Kotsinas A, Liloglou T et al. (2005). Nature 434: 907–913.
Holliday R . (1987). Science 238: 163–170.
Huang L, Snyder AR, Morgan WF . (2003). Oncogene 22: 5848–5854.
Jackson AL, Loeb LA . (2001). Mutat Res 477: 7–21.
Kassie F, Parzefall W, Knasmuller S . (2000). Mutat Res 463: 13–31.
Loeb LA, Loeb KR, Anderson JP . (2003). Proc Natl Acad Sci USA 100: 776–781.
Lorenti Garcia C, Darroudi F, Tates AD, Natarajan AT . (2001). Mutat Res 492: 59–67.
Lorimore SA, Coates PJ, Wright EG . (2003). Oncogene 22: 7058–7069.
Morgan WF . (2003a). Radiat Res 159: 567–580.
Morgan WF . (2003b). Radiat Res 159: 581–596.
Niwa O, Kominami R . (2001). Proc Natl Acad Sci USA 98: 1705–1710.
Nomura T . (2003). Mutat Res 544: 425–432.
Rothkamm K, Löbrich M . (2003). Proc Natl Acad Sci USA 100: 5057–5062.
Sancar A, Lindsey-Boltz LA, Unsal-Kacman K, Linn S . (2004). Annu Rev Biochem 73: 39–85.
Shiraishi K, Shimura T, Taga M, Uematsu N, Gondo Y, Ohtaki M et al. (2002). Radiat Res 157: 661–667.
Tawn EJ, Whitehouse CA, Winther JF, Curwen GB, Rees GS, Stovall M et al. (2005). Mutat Res 583: 198–206.
Yauk CL, Dubrova YE, Grant GR, Jeffreys AJ . (2002). Mutat Res 500: 147–156.
Zheng N, Monckton DG, Wilson G, Hagemeister F, Chakraborty R, Connor TH et al. (2000). Environ Mol Mutagen 36: 134–145.
Acknowledgements
This work was supported by grants from the Wellcome Trust, the European Commission and the Department of Energy (YED), Cancer Research UK and the Hope Foundation (GDDJ) and the European Union PEPFAC project (JMP).
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Barber, R., Hickenbotham, P., Hatch, T. et al. Radiation-induced transgenerational alterations in genome stability and DNA damage. Oncogene 25, 7336–7342 (2006). https://doi.org/10.1038/sj.onc.1209723
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DOI: https://doi.org/10.1038/sj.onc.1209723
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