电离辐射诱发小肠粘膜上皮细胞损伤修复过程中基因组不稳定性及骨髓细胞染色体畸变
|
摘要
第一部分
体外培养的哺乳动物细胞在DNA损伤未完全修复的情况下可克服细胞检查点,携带DNA损伤进入细胞周期。本实验研究小肠粘膜高剂量电离辐射损伤后再生性修复过程中DNA损伤修复、基因组稳定性、细胞周期阻滞以及克服过程。
采用单次12GyX-射线腹部局部辐射小鼠诱发小肠粘膜上皮损伤后再生；采用γ-H2AX和53BP1foci作为DNA双链断裂的标志追踪隐窝干细胞内DNA双链断裂的动力学变化、DNA双链断裂修复能力以及遗传给子代细胞的能力；采用Ki67, c-myc免疫组化染色以及BrdU标记来反映隐窝干细胞的增殖状态；采用ATM, P53和Chk2等蛋白的激活来反应检查点的激活；采用H&E染色以及TUNEL实验来确认凋亡细胞。
结果表明：辐射后大量细胞凋亡,存活隐窝内细胞快速增殖形成微克隆。DNA双链断裂在粘膜再生起始时将至最低水平,然而在粘膜再生期升高,于此同时再生隐窝内细胞表现为染色体不稳定性。ATM-Chk2-P53通路在辐射后立即激活,在再生期ATM-Chk2-P53通路被抑制,细胞克服了检查点阻滞携带未修复的DNA损伤以及不稳定的染色体进入快速增殖状态。粘膜再生以及完整性恢复是以基因组不稳定性为代价。本实验提供了凋亡过程中DNA损伤修复蛋白位于凋亡细胞的体内证据,γ-H2AX存在于辐射后以及再生期的凋亡细胞内,而ATM, Chk2仅存在于再生期凋亡细胞内。
本实验表明：再生期基因组完整性的监视系统被抑制,使细胞增殖不受基因组损伤的干扰,再生期的快速增殖、粘膜完整性的快速恢复以基因组完整性为代价。
第二部分
重离子因其独特的剂量分布在肿瘤放射治疗中独具优势。本实验拟比较12C6+离子辐射与传统X-射线辐射诱发骨髓染色体畸变的差异。
采用兰州重离子研究装置(HIRFL)加速的12C6+离子和传统X射线全身辐照小鼠并于辐照后9h收集股骨骨髓细胞；分析gaps、terminal deletions、breaks、 fragments、inter-hromosomal fusions以及sister-chromatid union等畸类型；分别用线性模型以及线性平方模型来拟合两种辐射诱发染色体畸变的量效关系；剂量平均线能(dose-mean liner energy, y D)用来比较12C6+辐射和X射线辐射的微观剂量分布与相对生物效应(RBE)。
结果表明：每种类型的染色体畸变都呈剂量依赖性。线性平方模型可拟合两种辐射类型的量效关系,而线性模型仅可拟合12C6+辐射量效关系。二元辐射作用复合模型用来解释X-射线量效关系的高曲率。12C6+辐射后染色体畸变的分布较X-射线辐射不均匀,这种不均匀性归因于12C6+辐射径迹分布的不均匀以及径迹半影区内剂量分布的不均匀性。12C6+坪区与X射线在染色质尺度的剂量平均线能之比最接近相对生物效应(RBE)。
结论：射线在染色质范围内的微观剂量分布可更好的反应射线的品质。
PART.1:It has been reported that cultured mammalian cells cannot sustain cell cycle arrest in a long run after the number of DNA double strand breaks drop to a relative low level and enter mitosis with DNA breaks. Here we aimed at assess the checkpoint activation and cell cycle restarting in process of intestinal crypt regeneration.Crypt regeneration of intestine was induced by a single dose of12Gy abdominal irradiation. γ-H2AX,53BP1were used as DNA repair surrogates to investigate the inherent ability of crypt stem cells to recognize and repair double-strand breaks. The Ki67staining and5-bromo-2'-deoxyuridine incorporation assay were used to study patterns of cell proliferation in regenerating crypts and ATM, P53and Check2staining to study checkpoint activation and release. Apoptosis was evaluated by H&E staining and Terminal deoxynucleotidyl transferase dUTP nick end labeling.After reaching to very low levels after irradiation, the DSBs in crypt stem cells rose again in crypts underwent regeneration. A sudden rose of chromosomal bridges was also observed in this process. ATM-Chk2-P53pathway was activated immediately after irradiation. Nevertheless, to our surprise, this genomic surveillance pathway was depressed during the regeneration phase despite the presence of a second wave of DNA damage, including DSBs and chromosomal bridges, in the cells in the regenerating crypts.
The y-H2AX is present in early and late apoptotic cells whereras ATM, Chk2are present in early apoptotic cells not in apoptotic cells in regeneration phase. Intestinal stem cells can adapt to IR-induced checkpoint arrest before regeneration. ATM-Chk2-P53pathway was activated immediately after irradiation. Nevertheless, to our surprise, this genomic surveillance pathway was depressed during the regeneration phase despite the presence of a second wave of DNA damage.This process in characterized by chromosomal instability. It was switch to reliance on mitotic cell death rather than on cell cycle delay or apoptosis to eliminate the cells with severe DNA damage or CIN that would prevent cell division.The DNA damage response proteins such as ATM, Chk2,53BP1,γ-H2AX are present in apoptotic cells or apoptototic bodies.
PART.2:For radiation induced bone marrow chromosomal aberration studies, the whole bodies of6-week-old male Kun-Ming mice were exposed to different doses of12C6+ion or x-rays. Chromosomal aberrations of bone marrow (gaps, terminal deletions and breaks, fragments, inter-hromosomal fusions and sister-chromatid union) were scored in metaphase at9hour after exposure corresponded to cells exposed in the G2-phase of first mitosis cycle. Dose-response relationships for frequency of chromosomal aberrations were plotted both by linear and linear-quadratic equations. The data showed that there was a dose-related increase in frequency of chromosomal aberrations in all treated groups compared to controls. Linear-quadratic equation was well fitted by both radiation qualities. The compound theory of dual radiation action was applied to decipher the bigger curvature (D2) of x-rays dose-response curves compared to12C6+ion. Different distribution of the five types of aberrations and different degree of homogeneity have been found between12C6+ion and x-rays irradiations and the possible underlying mechanism for these phenomena had been analysed according to the differences in the spatial energy deposition of both radiation qualities.
体外培养的哺乳动物细胞在DNA损伤未完全修复的情况下可克服细胞检查点,携带DNA损伤进入细胞周期。本实验研究小肠粘膜高剂量电离辐射损伤后再生性修复过程中DNA损伤修复、基因组稳定性、细胞周期阻滞以及克服过程。
采用单次12GyX-射线腹部局部辐射小鼠诱发小肠粘膜上皮损伤后再生；采用γ-H2AX和53BP1foci作为DNA双链断裂的标志追踪隐窝干细胞内DNA双链断裂的动力学变化、DNA双链断裂修复能力以及遗传给子代细胞的能力；采用Ki67, c-myc免疫组化染色以及BrdU标记来反映隐窝干细胞的增殖状态；采用ATM, P53和Chk2等蛋白的激活来反应检查点的激活；采用H&E染色以及TUNEL实验来确认凋亡细胞。
结果表明：辐射后大量细胞凋亡,存活隐窝内细胞快速增殖形成微克隆。DNA双链断裂在粘膜再生起始时将至最低水平,然而在粘膜再生期升高,于此同时再生隐窝内细胞表现为染色体不稳定性。ATM-Chk2-P53通路在辐射后立即激活,在再生期ATM-Chk2-P53通路被抑制,细胞克服了检查点阻滞携带未修复的DNA损伤以及不稳定的染色体进入快速增殖状态。粘膜再生以及完整性恢复是以基因组不稳定性为代价。本实验提供了凋亡过程中DNA损伤修复蛋白位于凋亡细胞的体内证据,γ-H2AX存在于辐射后以及再生期的凋亡细胞内,而ATM, Chk2仅存在于再生期凋亡细胞内。
本实验表明：再生期基因组完整性的监视系统被抑制,使细胞增殖不受基因组损伤的干扰,再生期的快速增殖、粘膜完整性的快速恢复以基因组完整性为代价。
第二部分
重离子因其独特的剂量分布在肿瘤放射治疗中独具优势。本实验拟比较12C6+离子辐射与传统X-射线辐射诱发骨髓染色体畸变的差异。
采用兰州重离子研究装置(HIRFL)加速的12C6+离子和传统X射线全身辐照小鼠并于辐照后9h收集股骨骨髓细胞；分析gaps、terminal deletions、breaks、 fragments、inter-hromosomal fusions以及sister-chromatid union等畸类型；分别用线性模型以及线性平方模型来拟合两种辐射诱发染色体畸变的量效关系；剂量平均线能(dose-mean liner energy, y D)用来比较12C6+辐射和X射线辐射的微观剂量分布与相对生物效应(RBE)。
结果表明：每种类型的染色体畸变都呈剂量依赖性。线性平方模型可拟合两种辐射类型的量效关系,而线性模型仅可拟合12C6+辐射量效关系。二元辐射作用复合模型用来解释X-射线量效关系的高曲率。12C6+辐射后染色体畸变的分布较X-射线辐射不均匀,这种不均匀性归因于12C6+辐射径迹分布的不均匀以及径迹半影区内剂量分布的不均匀性。12C6+坪区与X射线在染色质尺度的剂量平均线能之比最接近相对生物效应(RBE)。
结论：射线在染色质范围内的微观剂量分布可更好的反应射线的品质。
PART.1:It has been reported that cultured mammalian cells cannot sustain cell cycle arrest in a long run after the number of DNA double strand breaks drop to a relative low level and enter mitosis with DNA breaks. Here we aimed at assess the checkpoint activation and cell cycle restarting in process of intestinal crypt regeneration.Crypt regeneration of intestine was induced by a single dose of12Gy abdominal irradiation. γ-H2AX,53BP1were used as DNA repair surrogates to investigate the inherent ability of crypt stem cells to recognize and repair double-strand breaks. The Ki67staining and5-bromo-2'-deoxyuridine incorporation assay were used to study patterns of cell proliferation in regenerating crypts and ATM, P53and Check2staining to study checkpoint activation and release. Apoptosis was evaluated by H&E staining and Terminal deoxynucleotidyl transferase dUTP nick end labeling.After reaching to very low levels after irradiation, the DSBs in crypt stem cells rose again in crypts underwent regeneration. A sudden rose of chromosomal bridges was also observed in this process. ATM-Chk2-P53pathway was activated immediately after irradiation. Nevertheless, to our surprise, this genomic surveillance pathway was depressed during the regeneration phase despite the presence of a second wave of DNA damage, including DSBs and chromosomal bridges, in the cells in the regenerating crypts.
The y-H2AX is present in early and late apoptotic cells whereras ATM, Chk2are present in early apoptotic cells not in apoptotic cells in regeneration phase. Intestinal stem cells can adapt to IR-induced checkpoint arrest before regeneration. ATM-Chk2-P53pathway was activated immediately after irradiation. Nevertheless, to our surprise, this genomic surveillance pathway was depressed during the regeneration phase despite the presence of a second wave of DNA damage.This process in characterized by chromosomal instability. It was switch to reliance on mitotic cell death rather than on cell cycle delay or apoptosis to eliminate the cells with severe DNA damage or CIN that would prevent cell division.The DNA damage response proteins such as ATM, Chk2,53BP1,γ-H2AX are present in apoptotic cells or apoptototic bodies.
PART.2:For radiation induced bone marrow chromosomal aberration studies, the whole bodies of6-week-old male Kun-Ming mice were exposed to different doses of12C6+ion or x-rays. Chromosomal aberrations of bone marrow (gaps, terminal deletions and breaks, fragments, inter-hromosomal fusions and sister-chromatid union) were scored in metaphase at9hour after exposure corresponded to cells exposed in the G2-phase of first mitosis cycle. Dose-response relationships for frequency of chromosomal aberrations were plotted both by linear and linear-quadratic equations. The data showed that there was a dose-related increase in frequency of chromosomal aberrations in all treated groups compared to controls. Linear-quadratic equation was well fitted by both radiation qualities. The compound theory of dual radiation action was applied to decipher the bigger curvature (D2) of x-rays dose-response curves compared to12C6+ion. Different distribution of the five types of aberrations and different degree of homogeneity have been found between12C6+ion and x-rays irradiations and the possible underlying mechanism for these phenomena had been analysed according to the differences in the spatial energy deposition of both radiation qualities.
引文
[1]Abraham RT. Checkpoint signalling:focusing on 53BP1. Nat Cell Biol 2002;4:E277-E279.
[2]Altieri F, Grillo C, Maceroni M Chichiarelli S. DNA damage and repair:From molecular mechanisms to health implications. Antioxid Redox Sign 2008;10:891-937.
[3]Ashton GH, Morton JP, Myant K, et al. Focal adhesion kinase is required for intestinal regeneration and tumorigenesis downstream of Wnt/c-Myc signaling. Developmental cell 2010;19:259-269.
[4]Azzam EⅠ, de Toledo SM Little JB. Oxidative metabolism, gap junctions and the ionizing radiation-induced bystander effect. Oncogene 2003;22:7050-7057.
[5]Banath JP, Macphail SH Olive PL. Radiation sensitivity, H2AX phosphorylation, and kinetics of repair of DNA strand breaks in irradiated cervical cancer cell lines. Cancer Res 2004;64:7144-7149.
[6]Barre B Perkins ND. A cell cycle regulatory network controlling NF-kappa B subunit activity and function. Embo Journal 2007;26:4841-4855.
[7]Bartek J, Bartkova J Lukas J. DNA damage signalling guards against activated oncogenes and tumour progression. Oncogene 2007;26:7773-7779.
[8]Bartkova J, Horejsi Z, Koed K, et al. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 2005;434:864-870.
[9]Bartkova J, Rezaei N, Liontos M, et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 2006;444:633-637.
[10]Berkovich E Ginsberg D. ATM is a target for positive regulation by E2F-1. Oncogene 2003;22:161-167.
[11]Bhogal N, Jalali F Bristow RG. Microscopic imaging of DNA repair foci in irradiated normal tissues. International journal of radiation biology 2009;85:732-746.
[12]Chakraborty S, Stark JM, Sun CL, et al. Chronic myelogenous leukemia stem and progenitor cells demonstrate chromosomal instability related to repeated breakage-fusion-bridge cycles mediated by increased nonhomologous end joining. Blood 2012;119:6187-6197.
[13]Chang WP Little JB. Evidence That DNA Double-Strand Breaks Initiate the Phenotype of Delayed Reproductive Death in Chinese-Hamster Ovary Cells. Radiation research 1992;131:53-59.
[14]Ciccia A Elledge SJ. The DNA damage response:making it safe to play with knives. Molecular cell 2010;40:179-204.
[15]Egler RA, Fernandes E, Rothermund K, et al. Regulation of reactive oxygen species, DNA damage, and c-Myc function by peroxiredoxin 1. Oncogene 2005;24:8038-8050.
[16]Flint J, Craddock CF, Villegas A, et al. Healing of Broken Human-Chromosomes by the Addition of Telomeric Repeats. Am J Hum Genet 1994;55:505-512.
[17]Frankenberg-Schwager M. Review of repair kinetics for DNA damage induced in eukaryotic cells in vitro by ionizing radiation. Radiotherapy and oncology:journal of the European Society for Therapeutic Radiology and Oncology 1989;14:307-320.
[18]Fre S, Bardin A, Robine S Louvard D. Notch signaling in intestinal homeostasis across species:the cases of Drosophila, Zebrafish and the mouse. Experimental cell research 2011;317:2740-2747.
[19]Furuta T, Takemura H, Liao ZY, et al. Phosphorylation of histone H2AX and activation of Mrell, Rad50, and Nbsl in response to replication-dependent DNA double-strand breaks induced by mammalian DNA topoisomerase I cleavage complexes. The Journal of biological chemistry 2003;278:20303-20312.
[20]Gisselsson D, Jonson T, Petersen A, et al. Telomere dysfunction triggers extensive DNA fragmentation and evolution of complex chromosome abnormalities in human malignant tumors. Proceedings of the National Academy of Sciences of the United States of America 2001;98:12683-12688.
[21]Goodarzi AA, Jeggo P Lobrich M. The influence of heterochromatin on DNA double strand break repair:Getting the strong, silent type to relax. DNA Repair 2010;9:1273-1282.
[22]Goodhead DT. The Initial Physical Damage Produced by Ionizing-Radiations. International journal of radiation biology 1989;56:623-634.
[23]Gottifredi V Prives C. The S phase checkpoint:When the crowd meets at the fork. Semin Cell Dev Biol 2005;16:355-368.
[24]Gu J, Lu H, Tippin B, Shimazaki N, Goodman MF Lieber MR. XRCC4:DNA ligase IV can ligate incompatible DNA ends and can ligate across gaps. The EMBO journal 2007;26:1010-1023.
[25]Haegebarth A Clevers H. Wnt signaling, Igr5, and stem cells in the intestine and skin. The American journal of pathology 2009;174:715-721.
[26]Hanasoge S Ljungman M. H2AX phosphorylation after UV irradiation is triggered by DNA repair intermediates and is mediated by the ATR kinase. Carcinogenesis 2007;28:2298-2304.
[27]Harrison JC Haber JE. Surviving the breakup:The DNA damage checkpoint. Annual review of genetics 2006;40:209-235.
[28]Hartlerode AJ Scully R. Mechanisms of double-strand break repair in somatic mammalian cells (vol 423, pg 157,2009). Biochem J 2010:426:389-389.
[29]He XC, Zhang JW, Tong WG, et al. BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-beta-catenin signaling. Nat Genet 2004;36:1117-1121.
[30]Hirose Y, Katayama M, Mirzoeva OK, Berger MS Pieper RO. Akt activation suppresses Chk2-mediated, methylating agent-induced G(2) arrest and protects from temozolomide-induced mitotic catastrophe and cellular senescence. Cancer Res 2005;65:4861-4869.
[31]Huang L, Snyder AR Morgan WF. Radiation-induced genomic instability and its implications for radiation carcinogenesis. Oncogene 2003:22:5848-5854.
[32]Jackson SP. Sensing and repairing DNA double-strand breaks. Carcinogenesis 2002;23:687-696.
[33]Jackson SP Bartek J. The DNA-damage response in human biology and disease. Nature 2009;461:1071-1078.
[34]Jackson SP Jeggo PA. DNA double-strand break repair and V(D)J recombination: involvement of DNA-PK. Trends in biochemical sciences 1995;20:412-415.
[35]Jensen J, Pedersen EE, Galante P. et al. Control sf endodermal endocrine development by Hes-1. Nat Genet 2000;24:36-44.
[36]Kadhim MA, Macdonald DA, Goodhead DT, Lorimore SA, Marsden SJ Wright EG. Transmission of chromosomal instability after plutonium alpha-particle irradiation. Nature 1992;355:738-740.
[37]Kastan MB Bartek J. Cell-cycle checkpoints and cancer. Nature 2004;432:316-323.
[38]Kastan MB Berkovich E. P53:a two-faced cancer gene. Nat Cell Biol 2007;9:489-491.
[39]Kim GJ, Chandrasekaran K Morgan WF. Mitochondrial dysfunction, persistently elevated levels of reactive oxygen species and radiation-induced genomic instability:a review. Mutagenesis 2006;21:361-367.
[40]Kim GJ, Fiskum GM Morgan WF. A role for mitochondrial dysfunction in perpetuating radiation-induced genomic instability. Cancer Res 2006;66:10377-10383.
[41]Kimelman D Xu W. beta-Catenin destruction complex:insights and questions from a structural perspective. Oncogene 2006;25:7482-7491.
[42]Kuefner MA, Brand M, Engert C, Kappey H, Uder M Distel LV. The effect of calyculin A on the dephosphorylation of the histone gamma-H2AX after formation of X-ray-induced DNA double-strand breaks in human blood lymphocytes. International journal of radiation biology 2013.
[43]Kuhne M, Riballo E, Rief N, Rothkamm K, Jeggo PA Lobrich M. A double-strand break repair defect in ATM-deficient cells contributes to radiosensitivity. Cancer Res 2004;64:500-508.
[44]Kusch T, Florens L, MacDonald WH, et al. Acetylation by Tip60 is required for selective histone variant exchange at DNA lesions. Science 2004;306:2084-2087.
[45]Lavin MF. ATM and the Mrell complex combine to recognize and signal DNA double-strand breaks. Oncogene 2007;26:7749-7758.
[46]Lee SE, Pellicioli A, Malkova A, Foiani M Haber JE. The Saccharomyces recombination protein Tidlp is required for adaptation from G2/M arrest induced by a double-strand break. Curr Biol 2001; 11:1053-1057.
[47]Lengauer C. How do tumors make ends meet? Proceedings of the National Academy of Sciences of the United States of America 2001;98:12331-12333.
[48]Leroy C, Lee SE, Vaze MB, et al. PP2C phosphatases Ptc2 and Ptc3 are required for DNA checkpoint inactivation after a double-strand break (vol 11, pg 827,2003). Molecular cell 2003;11:1119-1119.
[49]Limoli CL, Giedzinski E, Morgan WF, Swarts SG, Jones GDD Hyun W. Persistent oxidative stress in chromosomally unstable cells. Cancer Res 2003;63:3107-3111.
[50]Little JB. Genomic instability and bystander effects:a historical perspective. Oncogene 2003;22:6978-6987.
[51]Lorimore SA, Coates PJ Wright EG. Radiation-induced genomic instability and bystander effects:inter-related nontargeted effects of exposure to ionizing radiation. Oncogene 2003;22:7058-7069.
[52]Lorimore SA Wright EG. Radiation-induced genomic instability and bystander effects: related inflammatory-type responses to radiation-induced stress and injury? A review. International journal of radiation biology 2003;79:15-25.
[53]Lu C, Shi Y, Wang Z, et al. Serum starvation induces H2AX phosphorylation to regulate apoptosis via p38 MAPK pathway. FEBS letters 2008;582:2703-2708.
[54]Lu CR, Zhu F, Cho YY, et al. Cell apoptosis:Requirement of H2AX in DNA ladder formation, but not for the activation of caspase-3. Molecular cell 2006;23:121-132.
[55]Lukas J, Lukas C Bartek J. Mammalian cell cycle checkpoints:signalling pathways and their organization in space and time. DNA Repair 2004;3:997-1007.
[56]Luo W, Zou HY, Jin LH, et al. Axin contains three separable domains that confer intramolecular, homodimeric, and heterodimeric interactions involved in distinct functions. Journal of Biological Chemistry 2005;280:5054-5060.
[57]Lupardus PJ Cimprich KA. Checkpoint adaptation:Molecular mechanisms uncovered. Cell 2004;117:555-556.
[58]Mahrhofer H, Burger S, Oppitz U, Flentje M Djuzenova CS. Radiation induced DNA damage and damage repair in human tumor and fibroblast cell lines assessed by histone H2AX phosphorylation. Int J Radiat Oncol 2006;64:573-580.
[59]Matsuoka S, Huang MX Elledge SJ. Linkage of ATM to cell cycle regulation by the Chk2 protein kinase. Science 1998;282:1893-1897.
[60]May R, Riehl TE, Hunt C, Sureban SM, Anant S Houchen CW. Identification of a novel putative gastrointestinal stem cell and adenoma stem cell marker, doublecortin and CaM kinase-like-1, following radiation injury and in adenomatous polyposis coli/multiple intestinal neoplasia mice. Stem Cells 2008;26:630-637.
[61]McClintock B. The stability of broken ends of chromosomes in zea mays. Genetics 1941;26:234-282.
[62]McLin VA, Henning SJ Jamrich M. The role of the visceral mesoderm in the development of the gastrointestinal tract. Gastroenterology 2009;136:2074-2091.
[63]Merritt AJ, Allen TD, Potten CS Hickman JA. Apoptosis in small intestinal epithelia from P53-null mice:Evidence for a delayed, P53-indepdendent G2/M-associated cell death after gamma-irradiation. Oncogene 1997;14:2759-2766.
[64]Merritt AJ, Potten CS, Kemp CJ, et al. The Role of P53 in Spontaneous and Radiation-Induced Apoptosis in the Gastrointestinal-Tract of Normal and P53-Deficient Mice. Cancer Res 1994;54:614-617.
[65]Mohrin M, Bourke E, Alexander D, et al. Hematopoietic Stem Cell Quiescence Promotes Error-Prone DNA Repair and Mutagenesis. Cell Stem Cell 2010;7:174-185.
[66]Morgan WF. Non-targeted and delayed effects of exposure to ionizing radiation:II. Radiation-induced genomic instability and bystander effects in vivo, clastogenic factors and transgenerational effects. Radiation research 2003; 159:581-596.
[67]Morrison AJ, Highland J, Krogan NJ, et al. INO80 and gamma-H2AX interaction links ATP-dependent chromatin remodeling to DNA damage repair. Cell 2004;119:767-775.
[68]Mothersill C Seymour CB. Radiation-induced bystander effects-implications for cancer. Nat Rev Cancer 2004;4:158-164.
[69]Mukherjee B, Kessinger C. Kobayashi J, et al. DNA-PK phosphorylates histone H2AX during apoptotic DNA fragmentation in mammalian cells. DNA Repair 2006;5:575-590.
[70]Neumann A A Reddel RR. Telomere maintenance and cancer-look, no telomerase. Nat Rev Cancer 2002;2:879-884.
[71]Niwa O. Induced genomic instability in irradiated germ cells and in the offspring; reconciling discrepancies among the human and animal studies. Oncogene 2003;22:7078-7086.
[72]Olive PL Banath JP. Phosphorylation of histone H2AX as a measure of radiosensitivity. Int J Radiat Oncol 2004;58:331-335.
[73]Potten CS. Extreme Sensitivity of Some Intestinal Crypt Cells to X and Gamma-Irradiation. Nature 1977;269:518-521.
[74]Potten CS. Radiation, the ideal cytotoxic agent for studying the cell biology of tissues such as the small intestine. Radiation research 2004;161:123-136.
[75]Powell DW, Mifflin RC, Valentich JD, Crowe SE, Saada JI West AB. Myofibroblasts. II. Intestinal subepithelial myofibroblasts. The American journal of physiology 1999;277:C183-201.
[76]Powers JT, Hong S, Mayhew CN, Rogers PM, Knudsen ES Johnson DG. E2F1 uses the ATM signaling pathway to induce P53 and Chk2 phosphorylation and apoptosis. Molecular cancer research:MCR 2004;2:203-214.
[77]Prise KM O'Sullivan JM. Radiation-induced bystander signalling in cancer therapy. Nat Rev Cancer 2009;9:351-360.
[78]Puc J, Keniry M, Li HS, et al. Lack of PTEN sequesters CHK1 and initiates genetic instability. Cancer Cell 2005;7:193-204.
[79]Reddy JP, Peddibhotla S, Bu W, et al. Defining the ATM-mediated barrier to tumorigenesis in somatic mammary cells following ErbB2 activation. Proceedings of the National Academy of Sciences of the United States of America 2010;107:3728-3733.
[80]Redon C, Boon C, Johnson K, Bonner WM Rogakou EP. Megabase chromatin domains involved in DNA double-strand breaks in vivo. Mol Biol Cell 1999;10:282a-282a.
[81]Rogakou EP, Boon C, Redon C Bonner WM. Megabase chromatin domains involved in DNA double-strand breaks in vivo. The Journal of cell biology 1999;146:905-916.
[82]Rogakou EP, Nieves-Neira W, Boon C, Pommier Y Bonner WM. Initiation of DNA fragmentation during apoptosis induces phosphorylation of H2AX histone at serine 139. Journal of Biological Chemistry 2000;275:9390-9395.
[83]Rogakou EP, Pilch DR, Orr AH, Ivanova VS Bonner WM. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. The Journal of biological chemistry 1998;273:5858-5868.
[84]Rogoff HA, Pickering MT, Debatis ME, Jones S Kowalik TF. E2F1 induces phosphorylation of P53 that is coincident with P53 accumulation and apoptosis. Mol Cell Biol 2002;22:5308-5318.
[85]Rogoff HA, Pickering MT, Frame FM, et al. Apoptosis associated with deregulated E2F activity is dependent on E2F1 and Atm/Nbs1/Chk2. Mol Cell Biol 2004;24:2968-2977.
[86]Rothkamm K, Kuhne M, Jeggo PA Lobrich M. Radiation-induced genomic rearrangements formed by nonhomologous end-joining of DNA double-strand breaks. Cancer Res 2001;61:3886-3893.
[87]Rothkamm K Lobrich M. Evidence for a lack of DNA double-strand break repair in human cells exposed to very low x-ray doses. Proceedings of the National Academy of Sciences of the United States of America 2003;100:5057-5062.
[88]Roy K, Kodama S, Suzuki K, Fukase K Watanabe M. Hypoxia relieves X-ray-induced delayed effects in normal human embryo cells. Radiation research 2000;154:659-666.
[89]Rube CE, Dong X, Kuhne M, et al. DNA double-strand break rejoining in complex normal tissues. International journal of radiation oncology, biology, physics 2008;72:1180-1187.
[90]Sandell LL Zakian VA. Loss of a Yeast Telomere-Arrest, Recovery, and Chromosome Loss. Cell 1993;75:729-739.
[91]Sato T, van Es JH, Snippert HJ, et al. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature 2011;469:415-418.
[92]Schonhoff SE, Giel-Moloney M Leiter AB. Minireview:Development and differentiation of gut endocrine cells. Endocrinology 2004;145:2639-2644.
[93]Scoville DH, Sato T, He XC Li L. Current view:intestinal stem cells and signaling. Gastroenterology 2008; 134:849-864.
[94]Shaker A Rubin DC. Intestinal stem cells and epithelial-mesenchymal interactions in the crypt and stem cell niche. Translational research:the journal of laboratory and clinical medicine 2010;156:180-187.
[95]Shrivastav M, De Haro LP Nickoloff JA. Regulation of DNA double-strand break repair pathway choice. Cell research 2008; 18:134-147.
[96]Solier S, Kohn KW, Scroggins B, et al. Heat shock protein 90 alpha (HSP90 alpha), a substrate and chaperone of DNA-PK necessary for the apoptotic response. Proceedings of the National Academy of Sciences of the United States of America 2012;109:12866-12872.
[97]Solier S Pommier Y. The apoptotic ring:a novel entity with phosphorylated histones H2AX and H2B and activated DNA damage response kinases. Cell Cycle 2009;8:1853-1859.
[98]Solier S, Sordet O, Kohn KW Pommier Y. Death receptor-induced activation of the Chk2- and histone H2AX-associated DNA damage response pathways. Mol Cell Biol 2009;29:68-82.
[99]Stiff T, O'Driscoll M, Rief N, Iwabuchi K, Lobrich M Jeggo PA. ATM and DNA-PK function redundantly to phosphorylate H2AX after exposure to ionizing radiation. Cancer Res 2004;64:2390-2396.
[100]Suzuki K, Yokoyama S, Waseda S, Kodama S Watanabe M. Delayed reactivation of P53 in the progeny of cells surviving ionizing radiation. Cancer Res 2003;63:936-941.
[101]Syljuasen RG. Checkpoint adaptation in human cells. Oncogene 2007;26:5833-5839.
[102]Syljuasen RG, Jensen S, Bartek J Lukas J. Adaptation to the ionizing radiation-induced G2 checkpoint occurs in human cells and depends on checkpoint kinase 1 and Polo-like kinase 1 kinases. Cancer Res 2006;66:10253-10257.
[103]Tian H, Biehs B, Warming S, et al. A reserve stem cell population in small intestine renders Lgr5-positive cells dispensable. Nature 2011;478:255-259.
[104]Toczyski DP, Galgoczy DJ Hartwell LH. CDC5 and CKII control adaptation to the yeast DNA damage checkpoint. Cell 1997;90:1097-1106.
[105]Toyokuni H, Maruo A, Suzuki K Watanabe M. The Contribution of Radiation-induced Large Deletion of the Genome to Chromosomal Instability. Radiation research 2009;171:198-203.
[106]Vafa O, Wade M, Kern S, et al. c-Myc can induce DNA damage, increase reactive oxygen species, and mitigate P53 function:A mechanism for oncogene-induced genetic instability. Molecular cell 2002;9:1031-1044.
[107]Valerie K Povirk LF. Regulation and mechanisms of mammalian double-strand break repair. Oncogene 2003;22:5792-5812.
[108]van Attikum H Gasser SM. The histone code at DNA breaks:A guide to repair? Nat Rev Mol Cell Bio 2005;6:757-765.
[109]van Es JH, van Gijn ME, Riccio O, et al. Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 2005;435:959-963.
[110]van Gent DC van der Burg M. Non-homologous end-joining, a sticky affair. Oncogene 2007;26:7731-7740.
[111]van Vugt MATM, Bras A Medema RH. Restarting the cell cycle when the checkpoint comes to a halt. Cancer Res 2005;65:7037-7040.
[112]Varley H, Di SJ, Scherer SW Royle NJ. Characterization of terminal deletions at 7q32 and 22q13.3 healed by de novo telomere addition. Am J Hum Genet 2000;67:610-622.
[113]Varley H, Pickett HA, FoxonJL, Reddel RR Royle NJ. Molecular characterization of inter-telomere and intra-telomere mutations in human ALT cells. Nat Genet 2002;30:301-305.
[114]Wilkie AOM, Lamb J, Harris PC, Finney RD Higgs DR. A Truncated Human Chromosome-16 Associated with Alpha-Thalassemia Is Stabilized by Addition of Telomeric Repeat (Ttaggg)N. Nature 1990;346:868-871.
[115]Wilson JW, Pritchard DM, Hickman JA Potten CS. Radiation-induced P53 and p21(WAF-1/CIP1) expression in the murine intestinal epithelium-Apoptosis and cell cycle arrest. American Journal of Pathology 1998; 153:899-909.
[116]Wright EG. Manifestations and mechanisms of non-targeted effects of ionizing radiation. Mutat Res-Fund Mol M 2010;687:28-33.
[117]Wright EG. Manifestations and mechanisms of non-targeted effects of ionizing radiation. Mutation research 2010;687:28-33.
[118]Xu B, Kim ST Kastan MB. Involvement of Brcal in S-phase and G(2)-phase checkpoints after ionizing irradiation. Mol Cell Biol 2001;21:3445-3450.
[119]Yan KS, Chia LA, Li X, et al. The intestinal stem cell markers Bmil and Lgr5 identify two functionally distinct populations. Proceedings of the National Academy of Sciences of the United States of America 2012; 109:466-471.
[120]Yan KS, Chia LA, Li XN, et al. The intestinal stem cell markers Bmil and Lgr5 identify two functionally distinct populations. Proceedings of the National Academy of Sciences of the United States of America 2012; 109:466-471.
[121]Yen TH Wright NA. The gastrointestinal tract stem cell niche. Stem cell reviews 2006;2:203-212.
[122]Yeung TM, Chia LA, Kosinski CM Kuo CJ. Regulation of self-renewal and differentiation by the intestinal stem cell niche. Cellular and molecular life sciences: CMLS 2011;68:2513-2523.
[123]Yoo HY, Kumagai A, Shevchenko A, Shevchenko A Dunphy WG. Adaptation of a DNA replication checkpoint response depends upon inactivation of Claspin by the Polo-like kinase. Cell 2004;117:575-588.
[124]Zhou BB Elledge SJ. The DNA damage response:putting checkpoints in perspective. Nature 2000;408:433-439.
[125]Zhu LQ, Gibson P, Currle DS, et al. Prominin 1 marks intestinal stem cells that are susceptible to neoplastic transformation. Nature 2009;457:603-U114.
[126]Zuo YH, Dang XH, Zhang HF, et al. Genomic Instability Induced by Ionizing Radiation in Human Hepatocytes. J Toxicol Env Heal A 2012;75:700-706
[127]R.E. Curtis, J.D. Boice, M. Stovall, L. Bernstein, E. Holowaty, S. Karjalainen, F. Langmark, P.C. Nasca, A.G. Schwartz, M.J. Schymura, H.H. Storm, P. Toogood, P. Weyer, W.C. Moloney, Relationship of Leukemia Risk to Radiation-Dose Following Cancer of the Uterine Corpus, J Natl Cancer I,86 (1994) 1315-1324.
[128]I. Shuryak, R.K. Sachs, L. Hlatky, M.P. Little, P. Hahnfeldt, D.J. Brenner, Radiation-induced leukemia at doses relevant to radiation therapy:Modeling mechanisms and estimating risks, J Natl Cancer I,98 (2006) 1794-1806.
[129]S.T. Traweek, M.L. Slovak, A.P. Nademanee, R.K. Brynes, J.C. Niland, S.J. Forman, Clonal Karyotypic Hematopoietic-Cell Abnormalities Occurring after Autologous Bone-Marrow Transplantation for Hodgkins-Disease and Non-Hodgkins-Lymphoma, Blood,84 (1994) 957-963.
[130]A. Chatterjee, H.J. Schaefer, Microdosimetric Structure of Heavy-Ion Tracks in Tissue, Radiat Environ Bioph,13 (1976) 215-227.
[131]A. Chatterjee, H.J. Schaefer, Microdosimetric Structure of Heavy-Ion Tracks in Tissue, Radiat Environ Bioph,13 (1976)215-227.
[132]M. Hultqvist, J.E. Lillhok, L. Lindborg, I. Gudowska, H. Nikjoo, Nanodosimetry in a C-12 ion beam using Monte Carlo simulations, Radiation Measurements,45 (2010) 1238-1241.
[133]A.L. Brooks, S. Bao, K. Rithidech, W.B. Chrisler, L.A. Couch, L.A. Braby, Induction and repair of HZE induced cytogenetic damage, Phys Medica,17 (2001) 183-184.
[134]K.N. Rithidech, M. Golightly, E. Whorton, Analysis of cell cycle in mouse bone marrow cells following acute in vivo exposure to 56Fe ions, J Radiat Res (Tokyo),49 (2008) 437-443.
[2]Altieri F, Grillo C, Maceroni M Chichiarelli S. DNA damage and repair:From molecular mechanisms to health implications. Antioxid Redox Sign 2008;10:891-937.
[3]Ashton GH, Morton JP, Myant K, et al. Focal adhesion kinase is required for intestinal regeneration and tumorigenesis downstream of Wnt/c-Myc signaling. Developmental cell 2010;19:259-269.
[4]Azzam EⅠ, de Toledo SM Little JB. Oxidative metabolism, gap junctions and the ionizing radiation-induced bystander effect. Oncogene 2003;22:7050-7057.
[5]Banath JP, Macphail SH Olive PL. Radiation sensitivity, H2AX phosphorylation, and kinetics of repair of DNA strand breaks in irradiated cervical cancer cell lines. Cancer Res 2004;64:7144-7149.
[6]Barre B Perkins ND. A cell cycle regulatory network controlling NF-kappa B subunit activity and function. Embo Journal 2007;26:4841-4855.
[7]Bartek J, Bartkova J Lukas J. DNA damage signalling guards against activated oncogenes and tumour progression. Oncogene 2007;26:7773-7779.
[8]Bartkova J, Horejsi Z, Koed K, et al. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 2005;434:864-870.
[9]Bartkova J, Rezaei N, Liontos M, et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 2006;444:633-637.
[10]Berkovich E Ginsberg D. ATM is a target for positive regulation by E2F-1. Oncogene 2003;22:161-167.
[11]Bhogal N, Jalali F Bristow RG. Microscopic imaging of DNA repair foci in irradiated normal tissues. International journal of radiation biology 2009;85:732-746.
[12]Chakraborty S, Stark JM, Sun CL, et al. Chronic myelogenous leukemia stem and progenitor cells demonstrate chromosomal instability related to repeated breakage-fusion-bridge cycles mediated by increased nonhomologous end joining. Blood 2012;119:6187-6197.
[13]Chang WP Little JB. Evidence That DNA Double-Strand Breaks Initiate the Phenotype of Delayed Reproductive Death in Chinese-Hamster Ovary Cells. Radiation research 1992;131:53-59.
[14]Ciccia A Elledge SJ. The DNA damage response:making it safe to play with knives. Molecular cell 2010;40:179-204.
[15]Egler RA, Fernandes E, Rothermund K, et al. Regulation of reactive oxygen species, DNA damage, and c-Myc function by peroxiredoxin 1. Oncogene 2005;24:8038-8050.
[16]Flint J, Craddock CF, Villegas A, et al. Healing of Broken Human-Chromosomes by the Addition of Telomeric Repeats. Am J Hum Genet 1994;55:505-512.
[17]Frankenberg-Schwager M. Review of repair kinetics for DNA damage induced in eukaryotic cells in vitro by ionizing radiation. Radiotherapy and oncology:journal of the European Society for Therapeutic Radiology and Oncology 1989;14:307-320.
[18]Fre S, Bardin A, Robine S Louvard D. Notch signaling in intestinal homeostasis across species:the cases of Drosophila, Zebrafish and the mouse. Experimental cell research 2011;317:2740-2747.
[19]Furuta T, Takemura H, Liao ZY, et al. Phosphorylation of histone H2AX and activation of Mrell, Rad50, and Nbsl in response to replication-dependent DNA double-strand breaks induced by mammalian DNA topoisomerase I cleavage complexes. The Journal of biological chemistry 2003;278:20303-20312.
[20]Gisselsson D, Jonson T, Petersen A, et al. Telomere dysfunction triggers extensive DNA fragmentation and evolution of complex chromosome abnormalities in human malignant tumors. Proceedings of the National Academy of Sciences of the United States of America 2001;98:12683-12688.
[21]Goodarzi AA, Jeggo P Lobrich M. The influence of heterochromatin on DNA double strand break repair:Getting the strong, silent type to relax. DNA Repair 2010;9:1273-1282.
[22]Goodhead DT. The Initial Physical Damage Produced by Ionizing-Radiations. International journal of radiation biology 1989;56:623-634.
[23]Gottifredi V Prives C. The S phase checkpoint:When the crowd meets at the fork. Semin Cell Dev Biol 2005;16:355-368.
[24]Gu J, Lu H, Tippin B, Shimazaki N, Goodman MF Lieber MR. XRCC4:DNA ligase IV can ligate incompatible DNA ends and can ligate across gaps. The EMBO journal 2007;26:1010-1023.
[25]Haegebarth A Clevers H. Wnt signaling, Igr5, and stem cells in the intestine and skin. The American journal of pathology 2009;174:715-721.
[26]Hanasoge S Ljungman M. H2AX phosphorylation after UV irradiation is triggered by DNA repair intermediates and is mediated by the ATR kinase. Carcinogenesis 2007;28:2298-2304.
[27]Harrison JC Haber JE. Surviving the breakup:The DNA damage checkpoint. Annual review of genetics 2006;40:209-235.
[28]Hartlerode AJ Scully R. Mechanisms of double-strand break repair in somatic mammalian cells (vol 423, pg 157,2009). Biochem J 2010:426:389-389.
[29]He XC, Zhang JW, Tong WG, et al. BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-beta-catenin signaling. Nat Genet 2004;36:1117-1121.
[30]Hirose Y, Katayama M, Mirzoeva OK, Berger MS Pieper RO. Akt activation suppresses Chk2-mediated, methylating agent-induced G(2) arrest and protects from temozolomide-induced mitotic catastrophe and cellular senescence. Cancer Res 2005;65:4861-4869.
[31]Huang L, Snyder AR Morgan WF. Radiation-induced genomic instability and its implications for radiation carcinogenesis. Oncogene 2003:22:5848-5854.
[32]Jackson SP. Sensing and repairing DNA double-strand breaks. Carcinogenesis 2002;23:687-696.
[33]Jackson SP Bartek J. The DNA-damage response in human biology and disease. Nature 2009;461:1071-1078.
[34]Jackson SP Jeggo PA. DNA double-strand break repair and V(D)J recombination: involvement of DNA-PK. Trends in biochemical sciences 1995;20:412-415.
[35]Jensen J, Pedersen EE, Galante P. et al. Control sf endodermal endocrine development by Hes-1. Nat Genet 2000;24:36-44.
[36]Kadhim MA, Macdonald DA, Goodhead DT, Lorimore SA, Marsden SJ Wright EG. Transmission of chromosomal instability after plutonium alpha-particle irradiation. Nature 1992;355:738-740.
[37]Kastan MB Bartek J. Cell-cycle checkpoints and cancer. Nature 2004;432:316-323.
[38]Kastan MB Berkovich E. P53:a two-faced cancer gene. Nat Cell Biol 2007;9:489-491.
[39]Kim GJ, Chandrasekaran K Morgan WF. Mitochondrial dysfunction, persistently elevated levels of reactive oxygen species and radiation-induced genomic instability:a review. Mutagenesis 2006;21:361-367.
[40]Kim GJ, Fiskum GM Morgan WF. A role for mitochondrial dysfunction in perpetuating radiation-induced genomic instability. Cancer Res 2006;66:10377-10383.
[41]Kimelman D Xu W. beta-Catenin destruction complex:insights and questions from a structural perspective. Oncogene 2006;25:7482-7491.
[42]Kuefner MA, Brand M, Engert C, Kappey H, Uder M Distel LV. The effect of calyculin A on the dephosphorylation of the histone gamma-H2AX after formation of X-ray-induced DNA double-strand breaks in human blood lymphocytes. International journal of radiation biology 2013.
[43]Kuhne M, Riballo E, Rief N, Rothkamm K, Jeggo PA Lobrich M. A double-strand break repair defect in ATM-deficient cells contributes to radiosensitivity. Cancer Res 2004;64:500-508.
[44]Kusch T, Florens L, MacDonald WH, et al. Acetylation by Tip60 is required for selective histone variant exchange at DNA lesions. Science 2004;306:2084-2087.
[45]Lavin MF. ATM and the Mrell complex combine to recognize and signal DNA double-strand breaks. Oncogene 2007;26:7749-7758.
[46]Lee SE, Pellicioli A, Malkova A, Foiani M Haber JE. The Saccharomyces recombination protein Tidlp is required for adaptation from G2/M arrest induced by a double-strand break. Curr Biol 2001; 11:1053-1057.
[47]Lengauer C. How do tumors make ends meet? Proceedings of the National Academy of Sciences of the United States of America 2001;98:12331-12333.
[48]Leroy C, Lee SE, Vaze MB, et al. PP2C phosphatases Ptc2 and Ptc3 are required for DNA checkpoint inactivation after a double-strand break (vol 11, pg 827,2003). Molecular cell 2003;11:1119-1119.
[49]Limoli CL, Giedzinski E, Morgan WF, Swarts SG, Jones GDD Hyun W. Persistent oxidative stress in chromosomally unstable cells. Cancer Res 2003;63:3107-3111.
[50]Little JB. Genomic instability and bystander effects:a historical perspective. Oncogene 2003;22:6978-6987.
[51]Lorimore SA, Coates PJ Wright EG. Radiation-induced genomic instability and bystander effects:inter-related nontargeted effects of exposure to ionizing radiation. Oncogene 2003;22:7058-7069.
[52]Lorimore SA Wright EG. Radiation-induced genomic instability and bystander effects: related inflammatory-type responses to radiation-induced stress and injury? A review. International journal of radiation biology 2003;79:15-25.
[53]Lu C, Shi Y, Wang Z, et al. Serum starvation induces H2AX phosphorylation to regulate apoptosis via p38 MAPK pathway. FEBS letters 2008;582:2703-2708.
[54]Lu CR, Zhu F, Cho YY, et al. Cell apoptosis:Requirement of H2AX in DNA ladder formation, but not for the activation of caspase-3. Molecular cell 2006;23:121-132.
[55]Lukas J, Lukas C Bartek J. Mammalian cell cycle checkpoints:signalling pathways and their organization in space and time. DNA Repair 2004;3:997-1007.
[56]Luo W, Zou HY, Jin LH, et al. Axin contains three separable domains that confer intramolecular, homodimeric, and heterodimeric interactions involved in distinct functions. Journal of Biological Chemistry 2005;280:5054-5060.
[57]Lupardus PJ Cimprich KA. Checkpoint adaptation:Molecular mechanisms uncovered. Cell 2004;117:555-556.
[58]Mahrhofer H, Burger S, Oppitz U, Flentje M Djuzenova CS. Radiation induced DNA damage and damage repair in human tumor and fibroblast cell lines assessed by histone H2AX phosphorylation. Int J Radiat Oncol 2006;64:573-580.
[59]Matsuoka S, Huang MX Elledge SJ. Linkage of ATM to cell cycle regulation by the Chk2 protein kinase. Science 1998;282:1893-1897.
[60]May R, Riehl TE, Hunt C, Sureban SM, Anant S Houchen CW. Identification of a novel putative gastrointestinal stem cell and adenoma stem cell marker, doublecortin and CaM kinase-like-1, following radiation injury and in adenomatous polyposis coli/multiple intestinal neoplasia mice. Stem Cells 2008;26:630-637.
[61]McClintock B. The stability of broken ends of chromosomes in zea mays. Genetics 1941;26:234-282.
[62]McLin VA, Henning SJ Jamrich M. The role of the visceral mesoderm in the development of the gastrointestinal tract. Gastroenterology 2009;136:2074-2091.
[63]Merritt AJ, Allen TD, Potten CS Hickman JA. Apoptosis in small intestinal epithelia from P53-null mice:Evidence for a delayed, P53-indepdendent G2/M-associated cell death after gamma-irradiation. Oncogene 1997;14:2759-2766.
[64]Merritt AJ, Potten CS, Kemp CJ, et al. The Role of P53 in Spontaneous and Radiation-Induced Apoptosis in the Gastrointestinal-Tract of Normal and P53-Deficient Mice. Cancer Res 1994;54:614-617.
[65]Mohrin M, Bourke E, Alexander D, et al. Hematopoietic Stem Cell Quiescence Promotes Error-Prone DNA Repair and Mutagenesis. Cell Stem Cell 2010;7:174-185.
[66]Morgan WF. Non-targeted and delayed effects of exposure to ionizing radiation:II. Radiation-induced genomic instability and bystander effects in vivo, clastogenic factors and transgenerational effects. Radiation research 2003; 159:581-596.
[67]Morrison AJ, Highland J, Krogan NJ, et al. INO80 and gamma-H2AX interaction links ATP-dependent chromatin remodeling to DNA damage repair. Cell 2004;119:767-775.
[68]Mothersill C Seymour CB. Radiation-induced bystander effects-implications for cancer. Nat Rev Cancer 2004;4:158-164.
[69]Mukherjee B, Kessinger C. Kobayashi J, et al. DNA-PK phosphorylates histone H2AX during apoptotic DNA fragmentation in mammalian cells. DNA Repair 2006;5:575-590.
[70]Neumann A A Reddel RR. Telomere maintenance and cancer-look, no telomerase. Nat Rev Cancer 2002;2:879-884.
[71]Niwa O. Induced genomic instability in irradiated germ cells and in the offspring; reconciling discrepancies among the human and animal studies. Oncogene 2003;22:7078-7086.
[72]Olive PL Banath JP. Phosphorylation of histone H2AX as a measure of radiosensitivity. Int J Radiat Oncol 2004;58:331-335.
[73]Potten CS. Extreme Sensitivity of Some Intestinal Crypt Cells to X and Gamma-Irradiation. Nature 1977;269:518-521.
[74]Potten CS. Radiation, the ideal cytotoxic agent for studying the cell biology of tissues such as the small intestine. Radiation research 2004;161:123-136.
[75]Powell DW, Mifflin RC, Valentich JD, Crowe SE, Saada JI West AB. Myofibroblasts. II. Intestinal subepithelial myofibroblasts. The American journal of physiology 1999;277:C183-201.
[76]Powers JT, Hong S, Mayhew CN, Rogers PM, Knudsen ES Johnson DG. E2F1 uses the ATM signaling pathway to induce P53 and Chk2 phosphorylation and apoptosis. Molecular cancer research:MCR 2004;2:203-214.
[77]Prise KM O'Sullivan JM. Radiation-induced bystander signalling in cancer therapy. Nat Rev Cancer 2009;9:351-360.
[78]Puc J, Keniry M, Li HS, et al. Lack of PTEN sequesters CHK1 and initiates genetic instability. Cancer Cell 2005;7:193-204.
[79]Reddy JP, Peddibhotla S, Bu W, et al. Defining the ATM-mediated barrier to tumorigenesis in somatic mammary cells following ErbB2 activation. Proceedings of the National Academy of Sciences of the United States of America 2010;107:3728-3733.
[80]Redon C, Boon C, Johnson K, Bonner WM Rogakou EP. Megabase chromatin domains involved in DNA double-strand breaks in vivo. Mol Biol Cell 1999;10:282a-282a.
[81]Rogakou EP, Boon C, Redon C Bonner WM. Megabase chromatin domains involved in DNA double-strand breaks in vivo. The Journal of cell biology 1999;146:905-916.
[82]Rogakou EP, Nieves-Neira W, Boon C, Pommier Y Bonner WM. Initiation of DNA fragmentation during apoptosis induces phosphorylation of H2AX histone at serine 139. Journal of Biological Chemistry 2000;275:9390-9395.
[83]Rogakou EP, Pilch DR, Orr AH, Ivanova VS Bonner WM. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. The Journal of biological chemistry 1998;273:5858-5868.
[84]Rogoff HA, Pickering MT, Debatis ME, Jones S Kowalik TF. E2F1 induces phosphorylation of P53 that is coincident with P53 accumulation and apoptosis. Mol Cell Biol 2002;22:5308-5318.
[85]Rogoff HA, Pickering MT, Frame FM, et al. Apoptosis associated with deregulated E2F activity is dependent on E2F1 and Atm/Nbs1/Chk2. Mol Cell Biol 2004;24:2968-2977.
[86]Rothkamm K, Kuhne M, Jeggo PA Lobrich M. Radiation-induced genomic rearrangements formed by nonhomologous end-joining of DNA double-strand breaks. Cancer Res 2001;61:3886-3893.
[87]Rothkamm K Lobrich M. Evidence for a lack of DNA double-strand break repair in human cells exposed to very low x-ray doses. Proceedings of the National Academy of Sciences of the United States of America 2003;100:5057-5062.
[88]Roy K, Kodama S, Suzuki K, Fukase K Watanabe M. Hypoxia relieves X-ray-induced delayed effects in normal human embryo cells. Radiation research 2000;154:659-666.
[89]Rube CE, Dong X, Kuhne M, et al. DNA double-strand break rejoining in complex normal tissues. International journal of radiation oncology, biology, physics 2008;72:1180-1187.
[90]Sandell LL Zakian VA. Loss of a Yeast Telomere-Arrest, Recovery, and Chromosome Loss. Cell 1993;75:729-739.
[91]Sato T, van Es JH, Snippert HJ, et al. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature 2011;469:415-418.
[92]Schonhoff SE, Giel-Moloney M Leiter AB. Minireview:Development and differentiation of gut endocrine cells. Endocrinology 2004;145:2639-2644.
[93]Scoville DH, Sato T, He XC Li L. Current view:intestinal stem cells and signaling. Gastroenterology 2008; 134:849-864.
[94]Shaker A Rubin DC. Intestinal stem cells and epithelial-mesenchymal interactions in the crypt and stem cell niche. Translational research:the journal of laboratory and clinical medicine 2010;156:180-187.
[95]Shrivastav M, De Haro LP Nickoloff JA. Regulation of DNA double-strand break repair pathway choice. Cell research 2008; 18:134-147.
[96]Solier S, Kohn KW, Scroggins B, et al. Heat shock protein 90 alpha (HSP90 alpha), a substrate and chaperone of DNA-PK necessary for the apoptotic response. Proceedings of the National Academy of Sciences of the United States of America 2012;109:12866-12872.
[97]Solier S Pommier Y. The apoptotic ring:a novel entity with phosphorylated histones H2AX and H2B and activated DNA damage response kinases. Cell Cycle 2009;8:1853-1859.
[98]Solier S, Sordet O, Kohn KW Pommier Y. Death receptor-induced activation of the Chk2- and histone H2AX-associated DNA damage response pathways. Mol Cell Biol 2009;29:68-82.
[99]Stiff T, O'Driscoll M, Rief N, Iwabuchi K, Lobrich M Jeggo PA. ATM and DNA-PK function redundantly to phosphorylate H2AX after exposure to ionizing radiation. Cancer Res 2004;64:2390-2396.
[100]Suzuki K, Yokoyama S, Waseda S, Kodama S Watanabe M. Delayed reactivation of P53 in the progeny of cells surviving ionizing radiation. Cancer Res 2003;63:936-941.
[101]Syljuasen RG. Checkpoint adaptation in human cells. Oncogene 2007;26:5833-5839.
[102]Syljuasen RG, Jensen S, Bartek J Lukas J. Adaptation to the ionizing radiation-induced G2 checkpoint occurs in human cells and depends on checkpoint kinase 1 and Polo-like kinase 1 kinases. Cancer Res 2006;66:10253-10257.
[103]Tian H, Biehs B, Warming S, et al. A reserve stem cell population in small intestine renders Lgr5-positive cells dispensable. Nature 2011;478:255-259.
[104]Toczyski DP, Galgoczy DJ Hartwell LH. CDC5 and CKII control adaptation to the yeast DNA damage checkpoint. Cell 1997;90:1097-1106.
[105]Toyokuni H, Maruo A, Suzuki K Watanabe M. The Contribution of Radiation-induced Large Deletion of the Genome to Chromosomal Instability. Radiation research 2009;171:198-203.
[106]Vafa O, Wade M, Kern S, et al. c-Myc can induce DNA damage, increase reactive oxygen species, and mitigate P53 function:A mechanism for oncogene-induced genetic instability. Molecular cell 2002;9:1031-1044.
[107]Valerie K Povirk LF. Regulation and mechanisms of mammalian double-strand break repair. Oncogene 2003;22:5792-5812.
[108]van Attikum H Gasser SM. The histone code at DNA breaks:A guide to repair? Nat Rev Mol Cell Bio 2005;6:757-765.
[109]van Es JH, van Gijn ME, Riccio O, et al. Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 2005;435:959-963.
[110]van Gent DC van der Burg M. Non-homologous end-joining, a sticky affair. Oncogene 2007;26:7731-7740.
[111]van Vugt MATM, Bras A Medema RH. Restarting the cell cycle when the checkpoint comes to a halt. Cancer Res 2005;65:7037-7040.
[112]Varley H, Di SJ, Scherer SW Royle NJ. Characterization of terminal deletions at 7q32 and 22q13.3 healed by de novo telomere addition. Am J Hum Genet 2000;67:610-622.
[113]Varley H, Pickett HA, FoxonJL, Reddel RR Royle NJ. Molecular characterization of inter-telomere and intra-telomere mutations in human ALT cells. Nat Genet 2002;30:301-305.
[114]Wilkie AOM, Lamb J, Harris PC, Finney RD Higgs DR. A Truncated Human Chromosome-16 Associated with Alpha-Thalassemia Is Stabilized by Addition of Telomeric Repeat (Ttaggg)N. Nature 1990;346:868-871.
[115]Wilson JW, Pritchard DM, Hickman JA Potten CS. Radiation-induced P53 and p21(WAF-1/CIP1) expression in the murine intestinal epithelium-Apoptosis and cell cycle arrest. American Journal of Pathology 1998; 153:899-909.
[116]Wright EG. Manifestations and mechanisms of non-targeted effects of ionizing radiation. Mutat Res-Fund Mol M 2010;687:28-33.
[117]Wright EG. Manifestations and mechanisms of non-targeted effects of ionizing radiation. Mutation research 2010;687:28-33.
[118]Xu B, Kim ST Kastan MB. Involvement of Brcal in S-phase and G(2)-phase checkpoints after ionizing irradiation. Mol Cell Biol 2001;21:3445-3450.
[119]Yan KS, Chia LA, Li X, et al. The intestinal stem cell markers Bmil and Lgr5 identify two functionally distinct populations. Proceedings of the National Academy of Sciences of the United States of America 2012; 109:466-471.
[120]Yan KS, Chia LA, Li XN, et al. The intestinal stem cell markers Bmil and Lgr5 identify two functionally distinct populations. Proceedings of the National Academy of Sciences of the United States of America 2012; 109:466-471.
[121]Yen TH Wright NA. The gastrointestinal tract stem cell niche. Stem cell reviews 2006;2:203-212.
[122]Yeung TM, Chia LA, Kosinski CM Kuo CJ. Regulation of self-renewal and differentiation by the intestinal stem cell niche. Cellular and molecular life sciences: CMLS 2011;68:2513-2523.
[123]Yoo HY, Kumagai A, Shevchenko A, Shevchenko A Dunphy WG. Adaptation of a DNA replication checkpoint response depends upon inactivation of Claspin by the Polo-like kinase. Cell 2004;117:575-588.
[124]Zhou BB Elledge SJ. The DNA damage response:putting checkpoints in perspective. Nature 2000;408:433-439.
[125]Zhu LQ, Gibson P, Currle DS, et al. Prominin 1 marks intestinal stem cells that are susceptible to neoplastic transformation. Nature 2009;457:603-U114.
[126]Zuo YH, Dang XH, Zhang HF, et al. Genomic Instability Induced by Ionizing Radiation in Human Hepatocytes. J Toxicol Env Heal A 2012;75:700-706
[127]R.E. Curtis, J.D. Boice, M. Stovall, L. Bernstein, E. Holowaty, S. Karjalainen, F. Langmark, P.C. Nasca, A.G. Schwartz, M.J. Schymura, H.H. Storm, P. Toogood, P. Weyer, W.C. Moloney, Relationship of Leukemia Risk to Radiation-Dose Following Cancer of the Uterine Corpus, J Natl Cancer I,86 (1994) 1315-1324.
[128]I. Shuryak, R.K. Sachs, L. Hlatky, M.P. Little, P. Hahnfeldt, D.J. Brenner, Radiation-induced leukemia at doses relevant to radiation therapy:Modeling mechanisms and estimating risks, J Natl Cancer I,98 (2006) 1794-1806.
[129]S.T. Traweek, M.L. Slovak, A.P. Nademanee, R.K. Brynes, J.C. Niland, S.J. Forman, Clonal Karyotypic Hematopoietic-Cell Abnormalities Occurring after Autologous Bone-Marrow Transplantation for Hodgkins-Disease and Non-Hodgkins-Lymphoma, Blood,84 (1994) 957-963.
[130]A. Chatterjee, H.J. Schaefer, Microdosimetric Structure of Heavy-Ion Tracks in Tissue, Radiat Environ Bioph,13 (1976) 215-227.
[131]A. Chatterjee, H.J. Schaefer, Microdosimetric Structure of Heavy-Ion Tracks in Tissue, Radiat Environ Bioph,13 (1976)215-227.
[132]M. Hultqvist, J.E. Lillhok, L. Lindborg, I. Gudowska, H. Nikjoo, Nanodosimetry in a C-12 ion beam using Monte Carlo simulations, Radiation Measurements,45 (2010) 1238-1241.
[133]A.L. Brooks, S. Bao, K. Rithidech, W.B. Chrisler, L.A. Couch, L.A. Braby, Induction and repair of HZE induced cytogenetic damage, Phys Medica,17 (2001) 183-184.
[134]K.N. Rithidech, M. Golightly, E. Whorton, Analysis of cell cycle in mouse bone marrow cells following acute in vivo exposure to 56Fe ions, J Radiat Res (Tokyo),49 (2008) 437-443.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |