Reduced contribution of thermally labile sugar lesions to DNA double strand breakformation after exposure to heavy ions

Radiation Oncology

George Iliakis²  Gisela Taucher-Scholz¹  Burkhard Jakob¹  Emil Mladenov²  Alena Bencsik-Theilen²  Satyendra K Singh² 

[1] GSI Helmholtzzentrum für Schwerionenforschung GmbH, Division ofBiophysics, Darmstadt, Germany;Institute of Medical Radiation Biology, University of Duisburg-Essen MedicalSchool, Hufelandstr 55, Essen, 45122, Germany

关键词: Radiation chemistry;    Labile lesions;    Heavy ions;    High LET;    Ionizing radiation (IR);    DNA double strand breaks (DSB);   

Others  :  1154275
DOI  :  10.1186/1748-717X-8-77

 received in 2012-12-20, accepted in 2013-03-22,  发布年份 2013

【 摘 要 】

In cells exposed to low linear energy transfer (LET) ionizing-radiation (IR), double-strand-breaks (DSBs) form within clustered-damage-sites (CDSs) from lesions disrupting the DNA sugar-phosphate backbone. It is commonly assumed that all DSBs form promptly and are immediately detected by the cellular DNA-damage-response (DDR) apparatus. However, there is evidence that the pool of DSBs detected by physical methods, such as pulsed-field gel electrophoresis (PFGE), comprises not only promptly forming DSBs (prDSBs) but also DSBs developing during lysis at high temperatures from thermally-labile sugar-lesions (TLSLs). We recently demonstrated that conversion of TLSLs to DNA breaks and ultimately to DSBs also occurs in cells during the first hour of post-irradiation incubation at physiological temperatures. Thus, TLSL-dependent DSBs (tlDSBs) are not an avoidable technique-related artifact, but a reality the cell always faces. The biological consequences of tlDSBs and the dependence of their formation on LET require in-depth investigation. Heavy-ions (HI) are a promising high-LET radiation modality used in cancer treatment. HI are also encountered in space and generate serious radiation protection problems to prolonged space missions. Here, we study, therefore, the effect of HI on the yields of tlDSBs and prDSBs. We report a reduction in the yield of tlDBSs stronger than that earlier reported for neutrons, and with pronounced cell line dependence. We conclude that with increasing LET the complexity of CDSs increases resulting in a commensurate increase in the yield prDSBs and a decrease in tlDSBs. The consequences of these effects to the relative biological effectiveness are discussed.

【 授权许可】

   
2013 Singh et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

【 参考文献 】

• [1]Goodhead DT: Initial events in the cellular effects of ionizing radiations: clustered damage in DNA. Int J Radiat Biol 1994, 65:7-17.
• [2]von Sonntag C: The chemical basis of radiation biology. London - New York Philadelphia: Taylor & Francis; 1987.
• [3]von Sonntag C: Free-radical-induced DNA damage and Its repair. Berlin -Heidelberg: Springer; 2006.
• [4]Ward JF: Biochemistry of DNA lesions. Radiat Res 1985, 104:S103-S111.
• [5]Ward JF: DNA damage produced by ionizing radiation in mammalian cells: identities, mechanisms of formation, and reparability. Prog Nucl Acid Res 1988, 35:95-125.
• [6]Brenner DJ, Ward JF: Constraints on energy deposition and target size of multiply damaged sites associated with DNA double-strand breaks. Int J Radiat Biol 1992, 61:737-748.
• [7]Georgakilas AG: Processing of DNA damage clusters in human cells: current status of knowledge. Mol Biosyst 2008, 4:30-35.
• [8]O'Neill P, Wardman P: Radiation chemistry comes before radiation biology. Int J Radiat Biol 2009, 85:9-25.
• [9]Jackson SP, Bartek J: The DNA-damage response in human biology and disease. Nature 2009, 461:1071-1078.
• [10]Jones GD, Boswell TV, Ward JF: Effects of postirradiation temperature on the yields of radiation-induced single- and double-strand breakage in SV40 DNA. Radiat Res 1994, 138:291-296.
• [11]Lafleur MVM, Woldhuis J, Loman H: Alkali-labile sites and post-irradiation effects in gamma-irradiated biologically active double-stranded DNA in aqueous solution. Int J Radiat Biol 1979, 36:241-247.
• [12]Henle ES, Roots R, Holley WR, Chatterjee A: DNA strand breakage is correlated with unaltered base release after gamma irradiation. Radiat Res 1995, 143:144-150.
• [13]Fung H, Demple B: Distinct roles of Ape1 protein in the repair of DNA damage induced by ionizing radiation or bleomycin. J Biol Chem 2011, 286:4968-4977.
• [14]Rydberg B: Radiation-induced heat-labile sites that convert into DNA double-strand breaks. Radiat Res 2000, 153:805-812.
• [15]Stenerlöw B, Karlsson KH, Cooper B, Rydberg B: Measurement of prompt DNA double-strand breaks in mammalian cells without including heat-labile sites: results for cells deficient in nonhomologous end joining. Radiat Res 2003, 159:502-510.
• [16]Karlsson KH, Stenerlöw B: Extensive ssDNA end formation at DNA double-strand breaks in non-homologous end-joining deficient cells during the S phase. BMC Mol Biol 2007, 8:97. BioMed Central Full Text
• [17]Singh SK, Wu W, Wu W, Wang M, Iliakis G: Extensive repair of DNA double-strand breaks in cells deficient in the DNA-PK dependent pathway of NHEJ after exclusion of heat-labile sites. Radiat Res 2009, 172:152-164.
• [18]Singh SK, Wang M, Staudt C, Iliakis G: Post-irradiation chemical processing of DNA damage generates double-strand breaks in cells already engaged in repair. Nucleic Acids Res 2011, 39:8416-8429.
• [19]Singh SK, Wu W, Stuschke M, Bockisch A, Iliakis G: Reduced contribution of thermally-labile sugar lesions to DNA double-strand break formation after exposure to neutrons. Radiat Res 2012, 178:581-590.
• [20]Durante M, Loeffler JS: Charged particles in radiation oncology. Nat Rev Clin Oncol 2010, 7:37-43.
• [21]Durante M, Cucinotta FA: Heavy ion carcinogenesis and human space exploration. Nat Rev Cancer 2008, 8:465-472.
• [22]Allalunis-Turner MJ, Zia PKY, Barron GM, Mirzayans R, Day RS III: Radiation-induced DNA damage and repair in cells of a radiosensitive human malignant glioma cell line. Radiat Res 1995, 144:288-293.
• [23]Frank KM, Sharpless NE, Gao Y, Sekiguchi JM, Fergson DO, Zhu C, Manis JP, Horner J, DePinho RA, Alt FW: DNA ligase IV deficiency in mice leads to defective neurogenesis and embryonic lethality via the p53 pathway. Mol Cell 2000, 5:993-1002.
• [24]DiBiase SJ, Zeng Z-C, Chen R, Hyslop T, Curran WJ Jr, Iliakis G: DNA-dependent protein kinase stimulates an independently active, nonhomologous, end-joining apparatus. Cancer Res 2000, 60:1245-1253.
• [25]Allalunis-Turner MJ, Barron GM, Day RS, Dobler KD, Mirzayans R: Isolation of two cell lines from a human malignant glioma specimen differing in sensitivity to radiation and chemotherapeutic drugs. Radiat Res 1993, 134:349-354.
• [26]Lees-Miller SP, Godbout R, Chan DW, Weinfeld M, Day RS III, Barron GM, Allalunis-Turner J: Absence of p350 subunit of DNA-activated protein kinase from a radiosensitive human cell line. Science 1995, 267:1183-1185.
• [27]Iliakis G: Backup pathways of NHEJ in cells of higher eukaryotes: cell cycle dependence. Radiother Oncol 2009, 92:310-315.
• [28]Iliakis G, Wu W, Wang M, Terzoudi GI, Pantelias GE: Backup pathways of nonhomologous End joining May have a dominant role in the formation of chromosome aberrations. In Chromosomal alterations. Edited by Obe G. Vijayalaxmi. Berlin, Heidelberg, New York: Springer Verlag; 2007:67-85. Repair/NHEJ/Reviews SD (Series Editor)
• [29]Iliakis G, Wang H, Perrault AR, Boecker W, Rosidi B, Windhofer F, Wu W, Guan J, Terzoudi G, Pantelias G: Mechanisms of DNA double strand break repair and chromosome aberration formation. Cytogenet Genome Res 2004, 104:14-20.
• [30]Zyuzikov NA, Prise KM, Zdzienicka MZ, Newman HC, Michael BD, Trott KR: The relationship between the RBE of alpha particles and the radiosensitivity of different mutations of chinese hamster cells. Radiat Environ Biophys 2001, 40:243-248.
• [31]Hill MA, Herdman MT, Stevens DL, Jones NJ, Thacker J, Goodhead DT: Relative sensitivities of repair-deficient mammalian cells for clonogenic survival after α-particle irradiation. Radiat Res 2004, 162:667-676.
• [32]Wang H, Wang X, Zhang P, Wang Y: The Ku-dependent non-homologous end-joining but not other repair pathway is inhibited by high linear energy transfer ionizing radiation. DNA Repair (Amst) 2008, 7:725-733.
• [33]Li Y, Qian H, Wang Y, Cucinotta FA: A stochastic model of DNA fragments rejoining. PLoS One 2012, 7:e44293.
• [34]Franken NA, Hovingh S, Ten Cate R, Krawczyk P, Stap J, Hoebe R, Aten J, Barendsen GW: Relative biological effectiveness of high linear energy transfer α-particles for the induction of DNA-double-strand breaks, chromosome aberrations and reproductive cell death in SW-1573 lung tumour cells. Oncol Rep 2012, 27:769-774.
• [35]Jeggo PA, Geuting V, Löbrich M: The role of homologous recombination in radiation-induced double-strand break repair. Radiother Oncol 2011, 101:7-12.
• [36]Newhauser WD, Durante M: Assessing the risk of second malignancies after modern radiotherapy. Nat Rev Cancer 2011, 11:438-448.
• [37]Cucinotta F, Durante M: Cancer risk from exposure to galactiv cosmic rays: implications for space exploration by humans beings. Lancet Oncol 2006, 7:431-435.