Abstract
Exposure of living systems to radiation results in a wide assortment of lesions, the most significant of is damage to genomic DNA which alter specific cell functions including cell proliferation. The radiation induced DNA damage investigation is one of the important area in biology, but still the information available regarding the effects of proton is very limited. In this report, we investigated the differential gene expression pattern of DNA damage signaling genes such as damaged DNA binding, repair, cell cycle arrest, checkpoints and apoptosis using quantitative real-time RT-PCR in proton exposed mouse brain tissues. The expression profiles showed significant changes in DNA damage related genes in 2 Gy proton exposed mouse brain tissues as compared to control brain tissues. Furthermore, we also show that significantly increased levels of apoptotic related genes, caspase-3 and 8 activities in these cells, suggesting that in addition to differential expression of DNA damage genes, the alteration of apoptosis related genes may also contribute to the radiation induced DNA damage followed by programmed cell death. In summary, our findings suggest that proton exposed cells undergo severe DNA damage which in turn destabilize the chromatin stability.
Similar content being viewed by others
References
Ames BN (1989) Endogenous oxidative DNA damage, aging, and cancer. Free Radical Res Commun 7:121–128
Barnett YA, Barnett CR (1998) DNA damage and mutation: contributors to the age-related alterations in T cell-mediated immune responses. Mech Ageing Dev 102:165–176
Loft S, Poulsen HE (1997) Cancer risk and oxidative DNA damage in man. J Mol Med 75:67–68
Mecocci P, MacGarvey U, Beal MJ (1994) Oxidative damage to mitochondrial DNA is increased in Alzheimer’s disease. Ann Neurol 36:747–751
Von Sonntag C (1987) New aspects in the free-radical chemistry of pyrimidine nucleobases. Free Radic Res Commun 2:217–224
Burrows CJ, Muller JG (1998) Oxidative nucleobase modifications leading to strand scission. Chem Rev 98:1109–1151
Cadet J, Douki T, Gasparutto D, Ravanat JL (2003) Oxidative damage to DNA: formation, measurement and biochemical features. Mutat Res 531:5–23
Scholes ML, Schuchmann MN, Von Sonntag C (1992) Enhancement of radiation-induced base release from nucleosides in alkaline solution: essential role of the O- radical. Int J Radiat Biol 61:443–449
Sharma KK, Purkayastha S, Bernhard WA (2007) Unaltered free base release from d (CGCGCG) 2 produced by the direct effect of ionizing radiation at 4 K and room temperature. Radiat Res 167:501–507
Kumar A, Sevilla MD (2008) The role of pi sigma* excited states in electron-induced DNA strand break formation: a time-dependent density functional theory study. J Am Chem Soc 130:2130–2131
Cooke M, Evans MD, DizDaroglu M, Lunec J (2003) Oxidative DNA damage: mechanisms, mutation, and disease. FASEB J 17:1195–1214
Perrier S, Hau J, Gasparutto D, Cadet J, Favier A, Ravana JL (2006) Characterization of lysine-guanine cross-links upon one-electron oxidation of a guanine-containing oligonucleotide in the presence of a trilysine peptide. J Am Chem Soc 128:5703–5710
Xu X, Muller JG, Ye Y, Burrows CJ (2008) DNA-protein cross-links between guanine and lysine depend on the mechanism of oxidation for formation of C5 vs C8 guanosine adducts. J Am Chem Soc 130:703–709
Bentle MS, Bey EA, Dong Y, Reinicke KE, Boothman DA (2006) New tricks for old drugs: the anticarcinogenic potential of DNA repairs inhibitors. J Mol Histol 37:203–218
Michod D, Widmann C (2007) DNA-damage sensitizers: potential new therapeutical tools to improve chemotherapy. Crit Rev Oncol Hematol 63:160–171
Antonelli F, Belli M, Campa A, Chatterjee A, Dini V, Esposito G, Rydberg B, Simone G, Tabocchini MA (2004) DNA fragmentation induced by Fe ions in human cells: shielding influence on spatially correlated damage. Adv Space Res 34:1353–1357
Schulthesis TE, Kun LE, Ang KK, Stephen LC (1995) Radiation response of central nervous system. Int J Radiat Oncol Biol Phys 31:1093–1112
Friedman WA, Bova FJ (1992) Linear accelerator radio surgery for arteriovenous malformations. J Neurosurg 77:832–841
Regis J, Barolomei F, Metellus P, Rey M, Genton P, Dravet C, Bureau M, Semah F, Gastaut JL, Chauvel P (1999) Radiosurgery for trigeminal neuralgia and epilepsy. Neurosurg Clin N Am 10:359–377
Finnberg N, Wambi C, Ware JH, Kennedy AR, El-Deiry WS (2008) Gamma-radiation (GR) triggers a unique gene expression profile associated with cell death compared to proton radiation (PR) in mice in vivo. Cancer Biol Ther 7:2023–2033
Lee KB, Kim KR, Huh TL, Lee YM (2008) Proton induces apoptosis of hypoxic tumor cells by the p53-dependent and p38/JNK MAPK signaling pathways. Int J Oncol 33:1247–1256
Yin E, Nelson D, Coleman MA, Peterson, Wyrobek AJ (2003) Gene expression changes in mouse brain after exposure to low-dose ionizing radiation. Int J Radiat Biol 79:759–775
Mahmoud-Ahmed AS, Atkinson S, Wong S (2006) Early gene expression profile in mouse brain after exposure to ionizing radiation. Radiat Res 165:142–154
Ravichandran P, Periyakaruppan A, Sadanandan B, Ramesh V, Hall JC, Jejelowo O, Ramesh GT (2009) Induction of apoptosis in Rat lungepithelial cells by multiwalled carbon nanotubes. J Biochem Mol Toxicol 23:333–344
Periakaruppan A, Kumar F, Sarkar S, Sharma SC, Ramesh GT (2007) Uranium induces oxidative stress in lung epithelial cells. Arch Toxicol 81:389–395
Manna SK, Sarkar S, Barr J, Wise K, Barrera EV, Jejelowo O, Rice-Ficht AC, Ramesh GT (2005) Single-walled carbon nanotube induces oxidative stress and activates nuclear transcription factor-kappaB in human keratinocytes. Nano Lett 5:1676–1684
Sharma CS, Sarkar S, Periyakaruppan A, Barr J, Wise K, Thomas R, Wilson BL, Ramesh GT (2007) Single-walled carbon nanotubes induces oxidative stress in rat lung epithelial cells. J Nanosci Nanotechnol 7:2466–2472
Mirnics K, Middleton FA, Stanwood GD, Lewis DA, Levitt P (2001) Disease-specific changes in regulator of G-protein signaling 4 (RGS4) expressions in schizophrenia. Mol Psychiatry 6:293–301
Fernandez-Teijeiro A, Betensky RA, Sturla LM, Kim JY, Tamayo P, Pomeroy SL (2004) Combining gene expression profiles and clinical parameters for risk stratification in medulloblastomas. J Clin Oncol 22:994–998
Blalock EM, Geddes JW, Chen KC, Porter NM, Markesbery WR, Landfield PW (2004) Incipient Alzheimer’s disease: microarray correlation analyses reveal major transcriptional and tumor suppressor responses. Proc Natl Acad Sci USA 101:2173–2178
Sigurdsson S, Van Komen S, Bussen W, Schild D, Albala JS, Sung P (2001) Mediator function of the human Rad51B-Rad51C complex in Rad51/RPA-catalyzed DNA strand exchange. Genes Dev 15:3308–3318
Friedenson B (2007) The BRCA1/2 pathway prevents hematologic cancers in addition to breast and ovarian cancers. BMC Cancer 7:152
Hoeijmakers JH (2001) Genome maintenance mechanisms for preventing cancer. Nature 411:366–374
Gilmore PM, Quinn JE, Mullan PB, Andrews HN, McCabe N, Carty M et al (2003) Role played by BRCA1 in regulating the cellular response to stress. Biochem Soc Trans 31:257–262
Schaetzlein S, Kodandaramireddy NR, Ju Z, Lechel A, Stepczynska A, Lilli DR, Clark AB, Rudolph C, Kuhnel F, Wei K, Schlegelberger B, Schirmacher P, Kunkel TA, Greenberg RA, Edelmann W, Rudolph KL (2007) Exonuclease-1 deletion impairs DNA damage signaling and prolongs lifespan of telomere-dysfunctional mice. Cell 130:863–877
Pei L (2001) Identification of c-myc as a down-stream target for pituitary tumor-transforming gene. J Biol Chem 276:8484–8491
Romero F, Gil-Bernabe AM, Saez C, Japon MA, Pintor-Toro JA, Tortolero M (2004) Securin is a target of the UV response pathway in mammalian cells. Mol Cell Biol 24:2720–2733
Kim DS, Franklyn JA, Smith VE, Stratford AL, Pemberton HN, Warfield A, Watkinson JC, Ishmail T, Wakelam MJO, McCabe CJ (2007) Securin induces genetic instability in colorectal cancer by inhibiting double-stranded DNA repair activity. Carcinogenesis 28:749–759
Zou H, McGarry TJ, Bernal T, Kirschner MW (1999) Identification of a vertebrate sister-chromatid separation inhibitor involved in transformation and tumorigenesis. Science 285:418–422
Saez C, Martinez-Brocca MA, Castilla C, Soto A, Navarro E, Tortolero M, Pintor-Toro JA, Japon MA (2006) Prognostic significance of human pituitary tumor-transforming gene immunohistochemical expression in differentiated thyroid cancer. J Clin Endocrinol Metab 91:1404–1409
Zhou Y, Mehta KR, Choi AP, Scolavino S, Zhang X (2003) DNA damage-induced inhibition of securin expression is mediated by p53. J Biol Chem 278:462–470
Acknowledgements
This work was supported by NASA funding NNX08BA47A: NCC-1-02038: NIH-1P20MD001822-1.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Baluchamy, S., Zhang, Y., Ravichandran, P. et al. Expression profile of DNA damage signaling genes in 2 Gy proton exposed mouse brain. Mol Cell Biochem 341, 207–215 (2010). https://doi.org/10.1007/s11010-010-0451-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11010-010-0451-4