Ionizing radiation-induced oxidative stress, epigenetic changes and genomic instability: The pivotal role of mitochondria

References

• Alhazzazi TY, Kamarajan P, Joo N, Huang JY, Verdin E, D’Silva NJ, Kapila YL. 2011. Sirtuin-3 (SIRT3), a novel potential therapeutic target for oral cancer. Cancer 117:1670–1678.
   PubMed Web of Science ®Google Scholar
• Arana ME, Kunkel TA. 2010. Mutator phenotypes due to DNA replication infidelity. Semin Cancer Biol 20:304–311.
   PubMed Web of Science ®Google Scholar
• Aykin-Burns N, Slane BG, Liu AT, Owens KM, O’Malley MS, Smith BJ, Domann FE, Spitz DR. 2011. Sensitivity to low-dose/low-LET ionizing radiation in mammalian cells harboring mutations in succinate dehydrogenase subunit C is governed by mitochondria-derived reactive oxygen species. Radiat Res 175:150–158.
   PubMed Web of Science ®Google Scholar
• Aypar U, Morgan WF, Baulch JE. 2011. Radiation-induced genomic instability: Are epigenetic mechanisms the missing link? Int J Radiat Biol 87:179–191.
   PubMed Web of Science ®Google Scholar
• Badeaux AI, Shi Y. 2013. Emerging roles for chromatin as a signal integration and storage platform. Nat Rev Mol Cell Biol 14:211–224.
   Web of Science ®Google Scholar
• Bai J, Cederbaum AI. 2001. Mitochondrial catalase and oxidative injury. Biol Signals Recept 10:189–199.
   PubMedGoogle Scholar
• Barjaktarovic Z, Schmaltz D, Shyla A, Azimzadeh O, Schulz S, Haagen J, Dorr W, Sarioglu H, Schafer A, Atkinson MJ, Zischka H, Tapio S. 2011. Radiation-induced signaling results in mitochondrial impairment in mouse heart at 4 weeks after exposure to X-rays. PLoS One 6:27811.
   PubMed Web of Science ®Google Scholar
• Baverstock K, Karotki AV. 2011. Towards a unifying theory of late stochastic effects of ionizing radiation. Mutat Res 718:1–9.
   PubMed Web of Science ®Google Scholar
• Belikova NA, Glumac A, Rafikov R, Jiang J, Greenberger JS, Kagan VE, Bayir H. 2009. Radioprotection by short-term oxidative preconditioning: Role of manganese superoxide dismutase. FEBS Lett 583:3437–3442.
   PubMed Web of Science ®Google Scholar
• Bellizzi D, D’Aquila P, Giordano M, Montesanto A, Passarino G. 2012. Global DNA methylation levels are modulated by mitochondrial DNA variants. Epigenomics 4:17–27.
   PubMed Web of Science ®Google Scholar
• Belyakov OV, Mitchell SA, Parikh D, Randers-Pehrson G, Marino SA, Amundson SA, Geard CR, Brenner DJ. 2005. Biological effects in unirradiated human tissue induced by radiation damage up to 1 mm away. Proc Natl Acad Sci USA 102:14203–14208.
   PubMed Web of Science ®Google Scholar
• Benard G, Bellance N, Jose C, Melser S, Nouette-Gaulain K, Rossignol R. 2010. Multi-site control and regulation of mitochondrial energy production. Biochim Biophys Acta 1797:698–709.
   PubMedGoogle Scholar
• Berman BP, Weisenberger DJ, Aman JF, Hinoue T, Ramjan Z, Liu Y, Noushmehr H, Lange CP, van Dijk CM, Tollenaar RA, Van Den Berg D, Laird PW. 2011. Regions of focal DNA hypermethylation and long-range hypomethylation in colorectal cancer coincide with nuclear lamina-associated domains. Nat Genet 44:40–46.
   PubMed Web of Science ®Google Scholar
• Biswas SK, Rahman I. 2009. Environmental toxicity, redox signaling and lung inflammation: The role of glutathione. Mol Aspects Med 30:60–76.
   PubMed Web of Science ®Google Scholar
• Bonekamp NA, Volkl A, Fahimi HD, Schrader M. 2009. Reactive oxygen species and peroxisomes: Struggling for balance. Biofactors 35:346–355.
   PubMed Web of Science ®Google Scholar
• Brady NR, Hamacher-Brady A, Westerhoff HV, Gottlieb RA. 2006. A wave of reactive oxygen species (ROS)-induced ROS release in a sea of excitable mitochondria. Antioxid Redox Signal 8:1651–1665.
   PubMed Web of Science ®Google Scholar
• Brand MD. 2010. The sites and topology of mitochondrial superoxide production. Exp Gerontol 45:466–472.
   PubMed Web of Science ®Google Scholar
• Brandes RP. 2005. Triggering mitochondrial radical release: A new function for NADPH oxidases. Hypertension 45:847–848.
   PubMed Web of Science ®Google Scholar
• Brenner DJ. 2012. Exploring two two-edged swords. Radiat Res 178: 7–16.
   PubMed Web of Science ®Google Scholar
• Bruzzone S, Parenti MD, Grozio A, Ballestrero A, Bauer I, Del RA, Nencioni A. 2013. Rejuvenating sirtuins: The rise of a new family of cancer drug targets. Curr Pharm Des 19:614–623.
   PubMed Web of Science ®Google Scholar
• Byrne HL, McNamara AL, Domanova W, Guatelli S, Kuncic Z. 2013. Radiation damage on sub-cellular scales: Beyond DNA. Phys Med Biol 58:1251–1267.
   PubMed Web of Science ®Google Scholar
• Candas D, Fan M, Nantajit D, Vaughan AT, Murley JS, Woloschak GE, Grdina DJ, Li JJ. 2013. CyclinB1/Cdk1 phosphorylates mitochondrial antioxidant MnSOD in cell adaptive response to radiation stress. J Mol Cell Biol 5:166–175.
   PubMed Web of Science ®Google Scholar
• Chaudhry MA, Omaruddin RA. 2012. Transcriptional changes of mitochondrial genes in irradiated cells proficient or deficient in p53. J Genet 91:105–110.
   PubMed Web of Science ®Google Scholar
• Chiba M. 2012. Radiation-responsive transcriptome analysis in human lymphoid cells. Radiat Prot Dosimetry 152:164–167.
   PubMed Web of Science ®Google Scholar
• Chinnery PF, Elliott HR, Hudson G, Samuels DC, Relton CL. 2012. Epigenetics, epidemiology and mitochondrial DNA diseases. Int J Epidemiol 41:177–187.
   PubMed Web of Science ®Google Scholar
• Choi KM, Kang CM, Cho ES, Kang SM, Lee SB, Um HD. 2007. Ionizing radiation-induced micronucleus formation is mediated by reactive oxygen species that are produced in a manner dependent on mitochondria, Nox1, and JNK. Oncol Rep 17:1183–1188.
   PubMed Web of Science ®Google Scholar
• Clutton SM, Townsend KM, Walker C, Ansell JD, Wright EG. 1996. Radiation-induced genomic instability and persisting oxidative stress in primary bone marrow cultures. Carcinogenesis 17: 1633–1639.
   PubMed Web of Science ®Google Scholar
• Collins-Underwood JR, Zhao W, Sharpe JG, Robbins ME. 2008. NADPH oxidase mediates radiation-induced oxidative stress in rat brain microvascular endothelial cells. Free Radic Biol Med 45:929–938.
   PubMed Web of Science ®Google Scholar
• Compton S, Kim C, Griner NB, Potluri P, Scheffler IE, Sen S, Jerry DJ, Schneider S, Yadava N. 2011. Mitochondrial dysfunction impairs tumor suppressor p53 expression /function. J Biol Chem 286:20297–20312.
   PubMed Web of Science ®Google Scholar
• D’Aquila P, Rose G, Panno ML, Passarino G, Bellizzi D. 2012. SIRT3 gene expression: A link between inherited mitochondrial DNA variants and oxidative stress. Gene 497:323–329.
   PubMed Web of Science ®Google Scholar
• Daiber A. 2010. Redox signaling (cross-talk) from and to mitochondria involves mitochondrial pores and reactive oxygen species. Biochim Biophys Acta 1797:897–906.
   PubMed Web of Science ®Google Scholar
• Datta K, Suman S, Kallakury BV, Fornace AJ Jr. 2012. Exposure to heavy ion radiation induces persistent oxidative stress in mouse intestine. PLoS One 7:e42224.
   PubMed Web of Science ®Google Scholar
• Dayal D, Martin SM, Limoli CL, Spitz DR. 2008. Hydrogen peroxide mediates the radiation-induced mutator phenotype in mammalian cells. Biochem J 413:185–191.
   PubMed Web of Science ®Google Scholar
• Dencher NA, Frenzel M, Reifschneider NH, Sugawa M, Krause F. 2007. Proteome alterations in rat mitochondria caused by aging. Ann NY Acad Sci 1100:291–298.
   PubMed Web of Science ®Google Scholar
• Der CJ. 1987. Cellular oncogenes and human carcinogenesis. Clin Chem 33:641–646.
   PubMed Web of Science ®Google Scholar
• Dhar SK, St Clair DK. 2012. Manganese superoxide dismutase regulation and cancer. Free Radic Biol Med 52:2209–2222.
   PubMed Web of Science ®Google Scholar
• Dickey JS, Zemp FJ, Martin OA, Kovalchuk O. 2011. The role of miRNA in the direct and indirect effects of ionizing radiation. Radiat Environ Biophys 50:491–499.
   PubMed Web of Science ®Google Scholar
• Ding N, Wu X, He J, Chang L, Hu W, Li W, Wang J, Wang T, Zhou G. 2011. Detection of novel human miRNAs responding to X-ray irradiation. J Radiat Res 52:425–432.
   PubMed Web of Science ®Google Scholar
• Doll R. 1995. Hazards of ionising radiation: 100 years of observations on man. Br J Cancer 72:1339–1349.
   PubMed Web of Science ®Google Scholar
• Drose S, Brandt U. 2012. Molecular mechanisms of superoxide production by the mitochondrial respiratory chain. Adv Exp Med Biol 748:145–169.
   PubMed Web of Science ®Google Scholar
• Dudkina NV, Kouril R, Peters K, Braun HP, Boekema EJ. 2010. Structure and function of mitochondrial supercomplexes. Biochim Biophys Acta 1797:664–670.
   PubMed Web of Science ®Google Scholar
• Eldridge A, Fan M, Woloschak G, Grdina DJ, Chromy BA, Li JJ. 2012. Manganese superoxide dismutase interacts with a large scale of cellular and mitochondrial proteins in low-dose radiation-induced adaptive radioprotection. Free Radic Biol Med 53: 1838–1847.
   Google Scholar
• Epperly MW, Gretton JE, Sikora CA, Jefferson M, Bernarding M, Nie S, Greenberger JS. 2003. Mitochondrial localization of superoxide dismutase is required for decreasing radiation-induced cellular damage. Radiat Res 160:568–578.
   PubMed Web of Science ®Google Scholar
• Fan M, Ahmed KM, Coleman MC, Spitz DR, Li JJ. 2007. Nuclear factor-kappaB and manganese superoxide dismutase mediate adaptive radioresistance in low-dose irradiated mouse skin epithelial cells. Cancer Res 67:3220–3228.
   PubMed Web of Science ®Google Scholar
• Ferrer-Sueta G, Radi R. 2007. Chemical biology of peroxynitrite: Kinetics, diffusion, and radicals. ACS Chem Biol 4:161–177.
   Web of Science ®Google Scholar
• Finley LW, Haigis MC. 2012. Metabolic regulation by SIRT3: Implications for tumorigenesis. Trends Mol Med 18:516–523.
   PubMed Web of Science ®Google Scholar
• Fransen M, Nordgren M, Wang B, Apanasets O, Van Veldhoven PP. 2013. Aging, age-related diseases and peroxisomes. Subcell Biochem 69:45–65.
   PubMedGoogle Scholar
• Gao S, Wu R, Zeng Y. 2012. Up-regulation of peroxisome proliferator-activated receptor gamma in radiation-induced heart injury in rats. Radiat Environ Biophys 51:53–59.
   PubMed Web of Science ®Google Scholar
• Georgakilas AG. 2012. Oxidative stress, DNA damage and repair in carcinogenesis: Have we established a connection? Cancer Lett 327:3–4.
   PubMed Web of Science ®Google Scholar
• Giralt A, Villarroya F. 2012. SIRT3, a pivotal actor in mitochondrial functions: Metabolism, cell death and aging. Biochem J 444:1–10.
   PubMed Web of Science ®Google Scholar
• Goetz ME, Luch A. 2008. Reactive species: A cell damaging rout assisting to chemical carcinogens. Cancer Lett 266:73–83.
   PubMed Web of Science ®Google Scholar
• Guha M, Avadhani NG. 2013. Mitochondrial retrograde signaling at the crossroads of tumor bioenergetics, genetics and epigenetics. Mitochondrion 13:577–591.
   Google Scholar
• Hake SB, Xiao A, Allis CD. 2004. Linking the epigenetic ‘language’ of covalent histone modifications to cancer. Br J Cancer 90:761–769.
   PubMed Web of Science ®Google Scholar
• Hamanaka RB, Chandel NS. 2010. Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes. Trends Biochem Sci 35:505–513.
   PubMed Web of Science ®Google Scholar
• Han D, Antunes F, Canali R, Rettori D, Cadenas E. 2003. Voltage- dependent anion channels control the release of the superoxide anion from mitochondria to cytosol. J Biol Chem 278:5557–5563.
   PubMed Web of Science ®Google Scholar
• Hanahan D, Weinberg RA. 2011. Hallmarks of cancer: The next generation. Cell 144:646–674.
   Google Scholar
• Hansen KD, Timp W, Bravo HC, Sabunciyan S, Langmead B, McDonald OG, Wen B, Wu H, Liu Y, Diep D, Briem E, Zhang K, Irizarry RA, Feinberg AP. 2011. Increased methylation variation in epigenetic domains across cancer types. Nat Genet 43:768–775.
   PubMed Web of Science ®Google Scholar
• Hasselbalch HC. 2013. Chronic inflammation as a promotor of mutagenesis in essential thrombocythemia, polycythemia vera and myelofibrosis. A human inflammation model for cancer development? Leuk Res 37:214–220.
   PubMed Web of Science ®Google Scholar
• Hassler MR, Egger G. 2012. Epigenomics of cancer – emerging new concepts. Biochimie 94:2219–2230.
   PubMed Web of Science ®Google Scholar
• Hermes M, Osswald H, Mattar J, Kloor D. 2004. Influence of an altered methylation potential on mRNA methylation and gene expression in HepG2 cells. Exp Cell Res 294:325–334.
   PubMed Web of Science ®Google Scholar
• Hitchler MJ, Wikainapakul K, Yu L, Powers K, Attatippaholkun W, Domann FE. 2006. Epigenetic regulation of manganese superoxide dismutase expression in human breast cancer cells. Epigenetics 1:163–171.
   PubMed Web of Science ®Google Scholar
• Hitchler MJ, Oberley LW, Domann FE. 2008. Epigenetic silencing of SOD2 by histone modifications in human breast cancer cells. Free Radic Biol Med 45:1573–1580.
   PubMed Web of Science ®Google Scholar
• Hosoki A, Yonekura S, Zhao QL, Wei ZL, Takasaki I, Tabuchi Y, Wang LL, Hasuike S, Nomura T, Tachibana A, Hashiguchi K, Yonei S, Kondo T, Zhang-Akiyama QM. 2012. Mitochondria-targeted superoxide dismutase (SOD2) regulates radiation resistance and radiation stress response in HeLa cells. J Radiat Res 53:58–71.
   PubMed Web of Science ®Google Scholar
• Iliou MS, Lujambio A, Portela A, Brustle O, Koch P, Andersson- Vincent PH, Sundstrom E, Hovatta O, Esteller M. 2011. Bivalent histone modifications in stem cells poise miRNA loci for CpG island hypermethylation in human cancer. Epigenetics 6:1344–1353.
   PubMed Web of Science ®Google Scholar
• Ilnytskyy Y, Koturbash I, Kovalchuk O. 2009. Radiation-induced bystander effects in vivo are epigenetically regulated in a tissue- specific manner. Environ Mol Mutagen 50:105–113.
   PubMed Web of Science ®Google Scholar
• Ilnytskyy Y, Kovalchuk O. 2011. Non-targeted radiation effects – an epigenetic connection. Mutat Res 714:113–125.
   PubMed Web of Science ®Google Scholar
• Jackson AL, Loeb LA. 2001. The contribution of endogenous sources of DNA damage to the multiple mutations in cancer. Mutat Res 477:7–21.
   PubMed Web of Science ®Google Scholar
• Janssen A, Medema RH. 2013. Genetic instability: Tipping the balance. Oncogene 32:459–4470.
   Web of Science ®Google Scholar
• Kadhim MA, Macdonald DA, Goodhead DT, Lorimore SA, Marsden SJ, Wright EG. 1992. Transmission of chromosomal instability after plutonium alpha-particle irradiation. Nature 355:738–740.
   PubMed Web of Science ®Google Scholar
• Kadhim M, Salomaa S, Wright E, Hildebrandt G, Belyakov OV, Prise KM, Little MP. 2013. Non-targeted effects of ionising radiation: Implications for low dose risk. Mutat Res 752:84–98.
   PubMed Web of Science ®Google Scholar
• Kam WW, Banati RB. 2013. Effects of ionizing radiation on mitochondria. Free Radic Biol Med 65C:607–619.
   Google Scholar
• Kamp DW, Shacter E, Weitzman SA. 2011. Chronic inflammation and cancer: The role of the mitochondria. Oncology 25:400–410, 413.
   PubMed Web of Science ®Google Scholar
• Kang MA, So EY, Simons AL, Spitz DR, Ouchi T. 2012. DNA damage induces reactive oxygen species generation through the H2AX-Nox1/Rac1 pathway. Cell Death Dis 3:e249.
   PubMed Web of Science ®Google Scholar
• Kaup S, Grandjean V, Mukherjee R, Kapoor A, Keyes E, Seymour CB, Mothersill CE, Schofield PN. 2006. Radiation-induced genomic instability is associated with DNA methylation changes in cultured human keratinocytes, Mutat Res 597:87–97.
   PubMed Web of Science ®Google Scholar
• Kazak L, Reyes A, Holt IJ. 2012. Minimizing the damage: Repair pathways keep mitochondrial DNA intact. Nat Rev Mol Cell Biol 13:659–671.
   PubMed Web of Science ®Google Scholar
• Kitagishi Y, Matsuda S. 2013. Redox regulation of tumor suppressor PTEN in cancer and aging (Review). Int J Mol Med 31:511–515.
   Google Scholar
• Klaunig JE, Wang Z, Pu X, Zhou S. 2011. Oxidative stress and oxidative damage in chemical carcinogenesis. Toxicol Appl Pharmacol 254:86–99.
   PubMed Web of Science ®Google Scholar
• Koturbash I, Pogribny I, Kovalchuk O. 2005. Stable loss of global DNA methylation in the radiation-target tissue – a possible mechanism contributing to radiation carcinogenesis? Biochem Biophys Res Commun 337:526–533.
   PubMed Web of Science ®Google Scholar
• Koturbash I, Baker M, Loree J, Kutanzi K, Hudson D, Pogribny I, Sedelnikova O, Bonner W, Kovalchuk O. 2006a. Epigenetic dysregulation underlies radiation-induced transgenerational genome instability in vivo. Int J Radiat Oncol Biol Phys 66:327–330.
   PubMed Web of Science ®Google Scholar
• Koturbash I, Rugo RE, Hendricks CA, Loree J, Thibault B, Kutanzi K, Pogribny I, Yanch JC, Engelward BP, Kovalchuk O. 2006b. Irradiation induces DNA damage and modulates epigenetic effectors in distant bystander tissue in vivo. Oncogene 25:4267–4275.
   PubMed Web of Science ®Google Scholar
• Kovalchuk O, Baulch JE. 2008. Epigenetic changes and nontargeted radiation effects – is there a link? Environ Mol Mutagen 49:16–25.
   PubMed Web of Science ®Google Scholar
• Kowaltowski AJ, Castilho RF, Vercesi AE. 2001. Mitochondrial permeability transition and oxidative stress. FEBS Lett 495:12–15.
   PubMed Web of Science ®Google Scholar
• Kryston TB, Georgiev AB, Pissis P, Georgakilas AG. 2011. Role of oxidative stress and DNA damage in human carcinogenesis. Mutat Res 711:193–201.
   PubMed Web of Science ®Google Scholar
• Kundu JK, Surh YJ. 2012. Emerging avenues linking inflammation and cancer. Free Radic Biol Med 52:2013–2037.
   PubMed Web of Science ®Google Scholar
• Kweon MH, Adhami VM, Lee JS, Mukhtar H. 2006. Constitutive overexpression of Nrf2-dependent heme oxygenase-1 in A549 cells contributes to resistance to apoptosis induced by epigallocatechin 3-gallate. J Biol Chem 281:33761–33772.
   PubMed Web of Science ®Google Scholar
• Larsen NB, Rasmussen M, Rasmussen LJ. 2005. Nuclear and mitochondrial DNA repair: Similar pathways? Mitochondrion 5:89–108.
   PubMed Web of Science ®Google Scholar
• Laurindo FR, Fernandes DC, Amanso AM, Lopes LR, Santos CX. 2008. Novel role of protein disulfide isomerase in the regulation of NADPH oxidase activity: Pathophysiological implications in vascular diseases. Antioxid Redox Signal 10:1101–1113.
   PubMed Web of Science ®Google Scholar
• Lawless MW, O’Byrne KJ, Gray SG. 2009. Oxidative stress induced lung cancer and COPD: Opportunities for epigenetic therapy. J Cell Mol Med 13:2800–2821.
   PubMed Web of Science ®Google Scholar
• Leach JK, Van TG, Lin PS, Schmidt-Ullrich R, Mikkelsen RB. 2001. Ionizing radiation-induced, mitochondria-dependent generation of reactive oxygen/nitrogen. Cancer Res 61:3894–3901.
   PubMed Web of Science ®Google Scholar
• Lebedeva MA, Eaton JS, Shadel GS. 2009. Loss of p53 causes mitochondrial DNA depletion and altered mitochondrial reactive oxygen species homeostasis. Biochim Biophys Acta 1787:328–334.
   PubMed Web of Science ®Google Scholar
• Lee HC, Chang CM, Chi CW. 2010. Somatic mutations of mitochondrial DNA in aging and cancer progression. Ageing Res Rev 9(Suppl. 1):S47–58.
   Google Scholar
• Lee J, Giordano S, Zhang J. 2012. Autophagy, mitochondria and oxidative stress: Cross-talk and redox signalling. Biochem J 441: 523–540.
   PubMed Web of Science ®Google Scholar
• Lenaz G, Genova ML. 2009. Structural and functional organization of the mitochondrial respiratory chain: A dynamic super-assembly. Int J Biochem Cell Biol 41:1750–1772.
   PubMed Web of Science ®Google Scholar
• Lenaz G, Genova ML. 2009. Mobility and function of coenzyme Q (ubiquinone) in the mitochondrial respiratory chain. Biochim Biophys Acta 1787:563–573.
   PubMed Web of Science ®Google Scholar
• Lenaz G, Genova ML. 2010. Structure and organization of mitochondrial respiratory complexes: A new understanding of an old subject. Antioxid Redox Signal 12:961–1008.
   PubMed Web of Science ®Google Scholar
• Lenaz G, Baracca A, Barbero G, Bergamini C, Dalmonte ME, Del SM, Faccioli M, Falasca A, Fato R, Genova ML, Sgarbi G, Solaini G. 2010. Mitochondrial respiratory chain super-complex I–III in physiology and pathology. Biochim Biophys Acta 1797:633–640.
   PubMedGoogle Scholar
• Lenaz G, Genova ML. 2012. Supramolecular organisation of the mitochondrial respiratory chain: A new challenge for the mechanism and control of oxidative phosphorylation. Adv Exp Med Biol 748:107–144.
   PubMed Web of Science ®Google Scholar
• Lertratanangkoon K, Wu CJ, Savaraj N, Thomas ML. 1997. Alterations of DNA methylation by glutathione depletion. Cancer Lett 120: 149–156.
   PubMed Web of Science ®Google Scholar
• Lim MJ, Ahn JY, Han Y, Yu CH, Kim MH, Lee SL, Lim DS, Song JY. 2012. Acriflavine enhances radiosensitivity of colon cancer cells through endoplasmic reticulum stress-mediated apoptosis. Int J Biochem Cell Biol 44:1214–1222.
   PubMed Web of Science ®Google Scholar
• Limoli CL, Hartmann A, Shephard L, Yang CR, Boothman DA, Bartholomew J, Morgan WF. 1998. Apoptosis, reproductive failure, and oxidative stress in Chinese hamster ovary cells with compromised genomic integrity. Cancer Res 58:3712–3718.
   PubMed Web of Science ®Google Scholar
• Limoli CL, Giedzinski E, Morgan WF, Swarts SG, Jones GD, Hyun W. 2003. Persistent oxidative stress in chromosomally unstable cells. Cancer Res 63:3107–3111.
   PubMed Web of Science ®Google Scholar
• Linard C, Gremy O, Benderitter M. 2008. Reduction of peroxisome proliferation-activated receptor gamma expression by gamma- irradiation as a mechanism contributing to inflammatory response in rat colon: Modulation by the 5-aminosalicylic acid agonist. J Pharmacol Exp Ther 324:911–920.
   PubMed Web of Science ®Google Scholar
• Little JB, Nagasawa H, Pfenning T, Vetrovs H. 1997. Radiation-induced genomic instability: Delayed mutagenic and cytogenetic effects of X rays and alpha particles. Radiat Res 148:299–307.
   PubMed Web of Science ®Google Scholar
• Little JB. Lauriston S. 2006. Taylor lecture: Nontargeted effects of radiation: Implications for low-dose exposures. Health Phys 91: 416–426.
   PubMed Web of Science ®Google Scholar
• Liu B, Chen Y, St Clair DK. 2008. ROS and p53: A versatile partnership. Free Radic Biol Med 44:1529–1535.
   PubMed Web of Science ®Google Scholar
• Liu P, Demple B. 2010. DNA repair in mammalian mitochondria: Much more than we thought? Environ Mol Mutagen 51:417–426.
   PubMed Web of Science ®Google Scholar
• Loeb LA. 2011. Human cancers express mutator phenotypes: Origin, consequences and targeting. Nat Rev Cancer 11:450–457.
   PubMed Web of Science ®Google Scholar
• Loree J, Koturbash I, Kutanzi K, Baker M, Pogribny I, Kovalchuk O. 2006. Radiation-induced molecular changes in rat mammary tissue: Possible implications for radiation-induced carcinogenesis. Int J Radiat Biol 82:805–815.
   PubMed Web of Science ®Google Scholar
• Luo B, Lee AS. 2013. The critical roles of endoplasmic reticulum chaperones and unfolded protein response in tumorigenesis and anticancer therapies. Oncogene 32:805–818.
   PubMed Web of Science ®Google Scholar
• Maillet A, Pervaiz S. 2012. Redox regulation of p53, redox effectors regulated by p53: A subtle balance. Antioxid Redox Signal 16: 1285–1294.
   PubMed Web of Science ®Google Scholar
• Malhotra JD, Kaufman RJ. 2007. The endoplasmic reticulum and the unfolded protein response. Semin Cell Dev Biol 18:716–731.
   PubMed Web of Science ®Google Scholar
• Malhotra JD, Kaufman RJ. 2011. ER stress and its functional link to mitochondria: Role in cell survival and death. Cold Spring Harb Perspect Biol 3:a004424.
   PubMed Web of Science ®Google Scholar
• Maranzana E, Barbero G, Falasca AI, Lenaz G, Genova ML. 2013. Mitochondrial respiratory supercomplex association limits production of reactive oxygen species from complex I. Antioxid Redox Signal 19:1469–1480.
   PubMed Web of Science ®Google Scholar
• Matsumoto H, Hamada N, Takahashi A, Kobayashi Y, Ohnishi T. 2007. Vanguards of paradigm shift in radiation biology: Radiation-induced adaptive and bystander responses. J Radiat Res 48:97–106.
   PubMed Web of Science ®Google Scholar
• Matsumoto H, Tomita M, Otsuka K, Hatashita M, Hamada N. 2011. Nitric oxide is a key molecule serving as a bridge between radiation-induced bystander and adaptive responses. Curr Mol Pharmacol 4:126–134.
   PubMedGoogle Scholar
• Medici V, Shibata NM, Kharbanda KK, LaSalle JM, Woods R, Liu S, Engelberg JA, Devaraj S, Torok NJ, Jiang JX, Havel PJ, Lonnerdal B, Kim K, Halsted CH. 2013. Wilson's disease: Changes in methionine metabolism and inflammation affect global DNA methylation in early liver disease. Hepatology 57:555–565.
   PubMed Web of Science ®Google Scholar
• Minocherhomji S, Tollefsbol TO, Singh KK. 2012. Mitochondrial regulation of epigenetics and its role in human diseases. Epigenetics 7:326–334.
   PubMed Web of Science ®Google Scholar
• Morgan WF. 2003. Is there a common mechanism underlying genomic instability, bystander effects and other nontargeted effects of exposure to ionizing radiation? Oncogene 22:7094–7099.
   PubMed Web of Science ®Google Scholar
• Mothersill C, Seymour CB. 1998. Cell-cell contact during gamma irradiation is not required to induce a bystander effect in normal human keratinocytes: Evidence for release during irradiation of a signal controlling survival into the medium. Radiat Res 149:256–262.
   PubMed Web of Science ®Google Scholar
• Murley JS, Kataoka Y, Cao D, Li JJ, Oberley LW, Grdina DJ. 2004. Delayed radioprotection by NFkappaB-mediated induction of Sod2 (MnSOD) in SA-NH tumor cells after exposure to clinically used thiol-containing drugs. Radiat Res 162:536–546.
   PubMed Web of Science ®Google Scholar
• Murley JS, Kataoka Y, Weydert CJ, Oberley LW, Grdina DJ. 2006. Delayed radioprotection by nuclear transcription factor kappaB-mediated induction of manganese superoxide dismutase in human microvascular endothelial cells after exposure to the free radical scavenger WR1065. Free Radic Biol Med 40:1004–1016.
   PubMed Web of Science ®Google Scholar
• Murnane JP. 1996. Role of induced genetic instability in the mutagenic effects of chemicals and radiation. Mutat Res 367:11–23.
   PubMed Web of Science ®Google Scholar
• Murphy JE, Nugent S, Seymour C, Mothersill C. 2005. Mitochondrial DNA point mutations and a novel deletion induced by direct low-LET radiation and by medium from irradiated cells. Mutat Res 585:127–136.
   PubMed Web of Science ®Google Scholar
• Murphy MP. 2009. How mitochondria produce reactive oxygen species. Biochem J 417:1–13.
   PubMed Web of Science ®Google Scholar
• Musselman CA, Lalonde ME, Cote J, Kutateladze TG. 2012. Perceiving the epigenetic landscape through histone readers. Nat Struct Mol Biol 19:1218–1227.
   PubMed Web of Science ®Google Scholar
• Naviaux RK. 2008. Mitochondrial control of epigenetics. Cancer Biol Ther 7:1191–1193.
   PubMed Web of Science ®Google Scholar
• Novak I. 2012. Mitophagy: A complex mechanism of mitochondrial removal. Antioxid Redox Signal 17:794–802.
   PubMed Web of Science ®Google Scholar
• Nowsheen S, Aziz K, Kryston TB, Ferguson NF, Georgakilas A. 2012. The interplay between inflammation and oxidative stress in carcinogenesis. Curr Mol Med 12:672–680.
   PubMed Web of Science ®Google Scholar
• Nugent SM, Mothersill CE, Seymour C, McClean B, Lyng FM, Murphy JE. 2007. Increased mitochondrial mass in cells with functionally compromised mitochondria after exposure to both direct gamma radiation and bystander factors. Radiat Res 168:134–142.
   PubMed Web of Science ®Google Scholar
• Nugent S, Mothersill CE, Seymour C, McClean B, Lyng FM, Murphy JE. 2010. Altered mitochondrial function and genome frequency post exposure to γ-radiation and bystander factors. Int J Radiat Biol 86:829–841.
   PubMed Web of Science ®Google Scholar
• O’Hagan HM, Mohammad HP, Baylin SB. 2008. Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter CpG island. PLoS Genet 4:e1000155.
   PubMed Web of Science ®Google Scholar
• O’Hagan HM, Wang W, Sen S, Destefano SC, Lee SS, Zhang YW, Clements EG, Cai Y, Van NL, Easwaran H, Casero RA, Sears CL, Baylin SB. 2011. Oxidative damage targets complexes containing DNA methyltransferases, SIRT1, and polycomb members to promoter CpG Islands. Cancer Cell 20:606–619.
   PubMed Web of Science ®Google Scholar
• Ohm JE, McGarvey KM, Yu X, Cheng L, Schuebel KE, Cope L, Mohammad HP, Chen W, Daniel VC, Yu W, Berman DM, Jenuwein T, Pruitt K, Sharkis SJ, Watkins DN, Herman JG, Baylin SB. 2007. A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing. Nat Genet 39:237–242.
   PubMed Web of Science ®Google Scholar
• Ozeki M, Tamae D, Hou DX, Wang T, Lebon T, Spitz DR, Li JJ. 2004. Response of cyclin B1 to ionizing radiation: Regulation by NF-kappaB and mitochondrial antioxidant enzyme MnSOD. Anticancer Res 24:2657–2663.
   PubMed Web of Science ®Google Scholar
• Park HS, Seong KM, Kim JY, Kim CS, Yang KH, Jin YW, Nam SY. 2013. Chronic low-dose radiation inhibits the cells death by cytotoxic high-dose radiation increasing the level of AKT and acinus proteins via NF-kappaB activation. Int J Radiat Biol 89:371–377.
   PubMed Web of Science ®Google Scholar
• Pazhanisamy SK, Li H, Wang Y, Batinic-Haberle I, Zhou D. 2011. NADPH oxidase inhibition attenuates total body irradiation-induced haematopoietic genomic instability. Mutagenesis 26:431–435.
   PubMed Web of Science ®Google Scholar
• Piccoli C, Ria R, Scrima R, Cela O, D’Aprile A, Boffoli D, Falzetti F, Tabilio A, Capitanio N. 2005. Characterization of mitochondrial and extra-mitochondrial oxygen consuming reactions in human hematopoietic stem cells. Novel evidence of the occurrence of NAD(P)H oxidase activity. J Biol Chem 280:26467–26476.
   PubMed Web of Science ®Google Scholar
• Pierce DA, Shimizu Y, Preston DL, Vaeth M, Mabuchi K. 1996. Studies of the mortality of atomic bomb survivors. Report 12, Part I. Cancer:1950–1990. Radiat Res 146:1–27.
   PubMed Web of Science ®Google Scholar
• Pierce DA, Vaeth M, Shimizu Y. 2007. Selection bias in cancer risk estimation from A-bomb survivors. Radiat Res 167:735–741.
   PubMed Web of Science ®Google Scholar
• Pierzchalski P, Krawiec A, Gawelko J, Pawlik WW, Konturek SJ, Gonciarz M. 2008. Molecular mechanism of protection against chemically and gamma-radiation induced apoptosis in human colon cancer cells. J Physiol Pharmacol 59(Suppl. 2):191–202.
   PubMedGoogle Scholar
• Pogribny I, Koturbash I, Tryndyak V, Hudson D, Stevenson SM, Sedelnikova O, Bonner W, Kovalchuk O. 2005. Fractionated low-dose radiation exposure leads to accumulation of DNA damage and profound alterations in DNA and histone methylation in the murine thymus. Mol Cancer Res 3:553–561.
   PubMed Web of Science ®Google Scholar
• Preston RJ. 2004. Radiation biology: Concepts for radiation protection. Health Phys 87:3–14.
   PubMed Web of Science ®Google Scholar
• Prise KM, Folkard M, Michael BD. 2006. Radiation-induced bystander and adaptive responses in cell and tissue models. Dose Response 4:263–276.
   PubMedGoogle Scholar
• Qu Y, Zhao S, Hong J, Tang S. 2010. Radiosensitive gene therapy through imRNA expression for silencing manganese superoxide dismutase. J Cancer Res Clin Oncol 136:953–959.
   PubMed Web of Science ®Google Scholar
• Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB. 2010. Oxidative stress, inflammation, and cancer: How are they linked? Free Radic Biol Med 49:1603–1616.
   PubMed Web of Science ®Google Scholar
• Riecke A, Rufa CG, Cordes M, Hartmann J, Meineke V, Abend M. 2012. Gene expression comparisons performed for biodosimetry purposes on in vitro peripheral blood cellular subsets and irradiated individuals. Radiat Res 178:234–243.
   PubMed Web of Science ®Google Scholar
• Rugo RE, Schiestl RH. 2004. Increases in oxidative stress in the progeny of X-irradiated cells. Radiat Res 162:416–425.
   PubMed Web of Science ®Google Scholar
• Rugo RE, Mutamba JT, Mohan KN, Yee T, Chaillet JR, Greenberger JS, Engelward BP. 2011. Methyltransferases mediate cell memory of a genotoxic insult. Oncogene 30:751–756.
   PubMed Web of Science ®Google Scholar
• Sandoval J, Esteller M. 2012. Cancer epigenomics: Beyond genomics. Curr Opin Genet Dev 22:50–55.
   PubMed Web of Science ®Google Scholar
• Santos CX, Tanaka LY, Wosniak J, Laurindo FR. 2009. Mechanisms and implications of reactive oxygen species generation during the unfolded protein response: Roles of endoplasmic reticulum oxidoreductases, mitochondrial electron transport, and NADPH oxidase. Antioxid Redox Signal 11:2409–2427.
   PubMed Web of Science ®Google Scholar
• Schafer E, Seelert H, Reifschneider NH, Krause F, Dencher NA, Vonck J. 2006. Architecture of active mammalian respiratory chain supercomplexes. J Biol Chem 281:15370–15375.
   PubMed Web of Science ®Google Scholar
• Schrader M, Fahimi HD. 2006. Peroxisomes and oxidative stress. Biochim Biophys Acta 1763:1755–1766.
   PubMed Web of Science ®Google Scholar
• Schroder M. 2008. Endoplasmic reticulum stress responses. Cell Mol Life Sci 65:862–894.
   PubMed Web of Science ®Google Scholar
• Schulz E, Wenzel P, Munzel T, Daiber A. 2014. Mitochondrial Redox Signaling: Interaction of mitochondrial reactive oxygen species with other sources of oxidative stress. Antioxid Redox Signal 20:308–324.
   PubMed Web of Science ®Google Scholar
• Sharma S, Kelly TK, Jones PA. 2010. Epigenetics in cancer. Carcinogenesis 31:27–36.
   PubMed Web of Science ®Google Scholar
• Shen L, Fang H, Chen T, He J, Zhang M, Wei X, Xin Y, Jiang Y, Ding Z, Ji J, Lu J, Bai Y. 2010. Evaluating mitochondrial DNA in cancer occurrence and development. Ann NY Acad Sci 1201:26–33.
   PubMed Web of Science ®Google Scholar
• Singh KK, Kulawiec M, Still I, Desouki MM, Geradts J, Matsui S. 2005. Inter-genomic cross talk between mitochondria and the nucleus plays an important role in tumorigenesis. Gene 354:140–146.
   PubMed Web of Science ®Google Scholar
• Singh KK, Kulawiec M. 2009. Mitochondrial DNA polymorphism and risk of cancer. Methods Mol Biol 471:291–303.
   PubMedGoogle Scholar
• Smiraglia DJ, Kulawiec M, Bistulfi GL, Gupta SG, Singh KK. 2008. A novel role for mitochondria in regulating epigenetic modification in the nucleus. Cancer Biol Ther 7:1182–1190.
   PubMed Web of Science ®Google Scholar
• Snyder AR, Morgan WF. 2004. Gene expression profiling after irradiation: Clues to understanding acute and persistent responses? Cancer Metastasis Rev 23:259–268.
   PubMed Web of Science ®Google Scholar
• Southgate TD, Sheard V, Milsom MD, Ward TH, Mairs RJ, Boyd M, Fairbairn LJ. 2006. Radioprotective gene therapy through retroviral expression of manganese superoxide dismutase. J Gene Med 8:557–565.
   PubMed Web of Science ®Google Scholar
• Sproul D, Kitchen RR, Nestor CE, Dixon JM, Sims AH, Harrison DJ, Ramsahoye BH, Meehan RR. 2012. Tissue of origin determines cancer-associated CpG island promoter hypermethylation patterns. Genome Biol 13:R84.
   PubMed Web of Science ®Google Scholar
• Steen HB. 2000. The origin of oncogenic mutations: Where is the primary damage? Carcinogenesis 21:1773–1776.
   PubMed Web of Science ®Google Scholar
• Streffer C. 2010. Strong association between cancer and genomic instability. Radiat Environ Biophys 49:125–131.
   PubMed Web of Science ®Google Scholar
• Su Z, Xia J, Zhao Z. 2011. Functional complementation between transcriptional methylation regulation and post-transcriptional microRNA regulation in the human genome. BMC Genomics 12(Suppl. 5):S15.
   PubMedGoogle Scholar
• Szumiel I. 2008. Intrinsic radiation sensitivity: Cellular signaling is the key. Radiat Res 169:249–258.
   PubMed Web of Science ®Google Scholar
• Takasugi M, Yagi S, Hirabayashi K, Shiota K. 2010. DNA methylation status of nuclear-encoded mitochondrial genes underlies the tissue-dependent mitochondrial functions. BMC Genomics 11:481–411.
   PubMed Web of Science ®Google Scholar
• Takeya R, Sumimoto H. 2006. Regulation of novel superoxide-producing NAD(P)H oxidases. Antioxid Redox Signal 8:1523–1532.
   PubMed Web of Science ®Google Scholar
• Tamminga J, Kovalchuk O. 2011. Role of DNA damage and epigenetic DNA methylation changes in radiation-induced genomic instability and bystander effects in germline in vivo. Curr Mol Pharmacol 4:115–125.
   PubMedGoogle Scholar
• Tao R, Coleman MC, Pennington JD, Ozden O, Park SH, Jiang H, Kim HS, Flynn CR, Hill S, Hayes MW, Olivier AK, Spitz DR, Gius D. 2010. Sirt3-mediated deacetylation of evolutionarily conserved lysine 122 regulates MnSOD activity in response to stress. Mol Cell 40:893–904.
   PubMed Web of Science ®Google Scholar
• Templin T, Paul S, Amundson SA, Young EF, Barker CA, Wolden SL, Smilenov LB. 2011. Radiation-induced micro-RNA expression changes in peripheral blood cells of radiotherapy patients. Int J Radiat Oncol Biol Phys 80:549–557.
   PubMed Web of Science ®Google Scholar
• Thomas SN, Waters KM, Morgan WF, Yang AJ, Baulch JE. 2012. Quantitative proteomic analysis of mitochondrial proteins reveals prosurvival mechanisms in the perpetuation of radiation-induced genomic instability. Free Radic Biol Med 53:618–628.
   PubMed Web of Science ®Google Scholar
• Timp W, Feinberg AP. 2013. Cancer as a dysregulated epigenome allowing cellular growth advantage at the expense of the host. Nat Rev Cancer 13:497–510.
   PubMed Web of Science ®Google Scholar
• Travis LB, Ng AK, Allan JM, Pui CH, Kennedy AR, Xu XG, Purdy JA, Applegate K, Yahalom J, Constine LS, Gilbert ES, Boice JD Jr. 2012. Second malignant neoplasms and cardiovascular disease following radiotherapy. J Natl Cancer Inst 104:357–370.
   PubMedGoogle Scholar
• Treberg JR, Quinlan CL, Brand MD. 2011. Evidence for two sites of superoxide production by mitochondrial NADH-ubiquinone oxidoreductase (complex I). J Biol Chem 286:27103–27110.
   PubMed Web of Science ®Google Scholar
• Turrens JF. 2003. Mitochondrial formation of reactive oxygen species. J Physiol 552 (Pt 2):335–344.
   PubMed Web of Science ®Google Scholar
• Vaissiere T, Sawan C, Herceg Z. 2008. Epigenetic interplay between histone modifications and DNA methylation in gene silencing. Mutat Res 659:40–48.
   PubMed Web of Science ®Google Scholar
• Valko M, Rhodes CJ, Moncol J, Izakovic M, Mazur M. 2006. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact 160:1–40.
   PubMed Web of Science ®Google Scholar
• Vendramini-Costa DB, Carvalho JE. 2012. Molecular link mechanisms between inflammation and cancer. Curr Pharm Des 18:3831–3852.
   PubMed Web of Science ®Google Scholar
• Vicente-Duenas C, Romero-Camarero I, Cobaleda C, Sanchez- Garcia I. 2013. Function of oncogenes in cancer development: A changing paradigm. EMBO J 32:1502–1513.
   PubMedGoogle Scholar
• Vire E, Brenner C, Deplus R, Blanchon L, Fraga M, Didelot C, Morey L, Van EA, Bernard D, Vanderwinden JM, Bollen M, Esteller M, Di CL, de LY, Fuks F. 2006. The Polycomb group protein EZH2 directly controls DNA methylation. Nature 439:871–874.
   PubMed Web of Science ®Google Scholar
• Vurusaner B, Poli G, Basaga H. 2012. Tumor suppressor genes and ROS: Complex networks of interactions. Free Rad Biol Med 52:7–18.
   PubMed Web of Science ®Google Scholar
• Wallace DC, Fan W. 2010. Energetics, epigenetics, mitochondrial genetics. Mitochondrion 10:12–31.
   PubMed Web of Science ®Google Scholar
• Wallace DC. 2012. Mitochondria and cancer. Nat Rev Cancer 12: 685–698.
   PubMed Web of Science ®Google Scholar
• Wang Y, Liu L, Pazhanisamy SK, Li H, Meng A, Zhou D. 2010. Total body irradiation causes residual bone marrow injury by induction of persistent oxidative stress in murine hematopoietic stem cells. Free Radic Biol Med 48:348–356.
   PubMed Web of Science ®Google Scholar
• Weinstein IB, Joe AK. 2006. Mechanisms of disease: Oncogene addiction – a rationale for molecular targeting in cancer therapy. Nat Clin Pract Oncol 3:448–457.
   PubMedGoogle Scholar
• Weyemi U, Redon CE, Parekh PR, Dupuy C, Bonner WM. 2013. NADPH oxidases NOXs and DUOXs as putative targets for cancer therapy. Anticancer Agents Med Chem 13:502–514.
   PubMed Web of Science ®Google Scholar
• Winge DR. 2012. Sealing the mitochondrial respirasome. Mol Cell Biol 32:2647–2652.
   PubMed Web of Science ®Google Scholar
• Yamamori T, Yasui H, Yamazumi M, Wada Y, Nakamura Y, Nakamura H, Inanami O. 2012. Ionizing radiation induces mitochondrial reactive oxygen species production accompanied by upregulation of mitochondrial electron transport chain function and mitochondrial content under control of the cell cycle checkpoint. Free Radic Biol Med 53:260–270.
   PubMed Web of Science ®Google Scholar
• Zhang B, Wang Y, Pang X, Su Y, Ai G, Wang T. 2010. ER stress induced by ionising radiation in IEC-6 cells. Int J Radiat Biol 86:429–435.
   PubMed Web of Science ®Google Scholar
• Zhao W, Robbins ME. 2009. Inflammation and chronic oxidative stress in radiation-induced late normal tissue injury: Therapeutic implications. Curr Med Chem 16:130–143.
   PubMed Web of Science ®Google Scholar
• Zorov DB, Juhaszova M, Sollott SJ. 2006. Mitochondrial ROS-induced ROS release: An update and review. Biochim Biophys Acta 1757: 509–517.
   PubMed Web of Science ®Google Scholar