Ts65Dn小鼠造血干细胞对辐射诱导DNA损伤修复障碍研究
|
摘要
唐氏综合症(Down Syndrome,DS)是人类常见的染色体疾病,患者有三条21号染色体,伴有肌肉、骨骼和神经发育异常,幼年患儿往往表现为造血系统异常,罹患急性巨核细胞白血病的几率增高。Ts65Dn小鼠与人类21号染色体有104个同源基因,与人类患者有相似的病理特症,例如学习和行为障碍,心脏病等,是目前常用的唐氏综合症模型。
研究表明非整倍体可能降低DNA损伤修复功能,引起基因组的不稳定性。唐氏综合症相关的造血系统异常和恶性肿瘤可能与造血干细胞(HSCs)自我更新能力受损,造血系统基因不稳定有关,为此我们利用唐氏综合症模型小鼠对Ts65Dn小鼠造血干细胞数量、功能及辐射诱导DNA损伤修复机制进行研究。研究发现与野生型对照小鼠(Wild type,WT)相比,Ts65Dn小鼠的骨髓造血干细胞HSCs数量明显减少,造血祖细胞(HPCs)水平没有明显变化；体外单细胞克隆实验结果显示Ts65Dn小鼠HSCs单细胞克隆形成率明显低于对照小鼠,表明Ts65Dn小鼠骨髓HSC数量减少、功能下降。利用γH2AX表达检测Ts65Dn小鼠HSC/HPC损伤DNA双链断裂(DSB),发现Ts65Dn小鼠γH2AX表达水平高于对照小鼠；体外2Gyγ射线照射后1小时,两种小鼠的HSCs的DSB水平没有差异,但是随着时间延长,照射后3小时和6小时后Ts65Dn小鼠的HSCs的未修复的DSB水平显著高于对照组小鼠。且照射后Ts65Dn小鼠HSCs的克隆形成能力显著降低。与对照小鼠相比,Ts65Dn小鼠造血祖细胞体外克隆能力和DSB水平以及照射后DSB修复能力没有显著差异。结果提示Ts65Dn小鼠在HSC水平出现了DNA损伤修复障碍及功能损伤。
USP16基因编码一种去泛素化酶,Ts65Dn小鼠因多余的基因拷贝表达过高的,USP16基因,可能是造血干细胞DSB修复缺陷的重要分子机制。应用RT-PCR两个不同探针检测发现,与WT相比,Ts65Dn小鼠HPC内USP16表达分别升高1.45倍和1.53倍。而HSC内USP16表达分别升高2.21倍和2.04倍。由于Ts65Dn小鼠HSC中USP16过高表达会引起H2A和H2AX的过度去泛素化,干扰双链断裂位置修复蛋白乳腺癌1号基因(BRCA1)复合体,p53结合蛋白(53BP1)等分子的招募,这可能与Ts65Dn小鼠HSC出现DSB修复障碍有关。
综上,我们应用Ts65Dn小鼠作为唐氏综合症动物研究模型,发现Ts65Dn小鼠的造血干细胞出现数量和功能的异常,辐射敏感性增加；Ts65Dn小鼠HSC出现DSB修复障碍,可能与USP16在Ts65Dn小鼠HSC中高表达有关。DSB的正常修复是维持基因稳定性的重要因素。本项研究结果表明Ts65Dn小鼠造血干细胞DSB修复障碍可能是唐氏综合症病人早年造血系统异常以及白血病高发的原因之一。USP16有可能成为唐氏综合症治疗中的潜在靶点。
Down syndrome (DS) is the most common chromosomal abnormality in humans caused by the presence of all or part of a third copy of chromosome21. In addition to musculoskeletal and neurodevelopmental abnormalities, pediatric patients with DS also display various hematologic disorders and are at increased risk of acute lymphoblastic leukemia and acute megakaryocytic leukemia. Ts65Dn mice are trisomic for104orthologs of the genes on human chromosome21and are one of the most widely used mouse models for DS research, because they exhibit various deficiencies similar to DS patients. It has been shown that aneuploidy can impair DNA damage repair and induce genomic instability. Therefore, we investigated whether hematopoietic stem cells (HSCs) from Ts65Dn mice are deficient in the repair of DNA double-strand breaks (DSBs), because the deficiency in the repair of DSBs in HSCs can potentially contribute to DS-associated hematological abnormalities and malignancies by impairing HSC self-renewal and inducing hematopoietic genetic instability. Our results showed that Ts65Dn mice had significantly less bone marrow HSCs than wild-type (WT) littermate controls, whereas the levels of bone marrow hematopoietic progenitor cells (HPCs) were similar. The lower level of HSCs in Ts65Dn mice was associated with a significantly higher level of DSBs as determined by γH2AX staining and lower level of clonogenic activity in single cell cultures with SCF, TPO and FL3ligand when compared to the cells from WT controls. Although levels of DSBs in HSCs were similar at1hr after exposure to2Gy y-irradiation in vitro, HSCs from Ts65Dn mice had significantly higher levels of unrepaired DSBs than the cells from WT mice at3and6hr after irradiation. Moreover, after exposure to2Gy y-irradiation in vitro, the reduction in clonogenic function was significantly greater in Ts65Dn HSCs than WT HSCs. In contrast, no significant differences in these parameters were observed in HPCs from Ts65Dn and WT mice with or without irradiation.
The molecular mechanism by which extra copy of chromosome21causes HSC defect in repair of DSBs remains to be elucidated. It may be attributable to an increased expression of USP16in Ts65Dn HSCs, because USP16is a deubiquitinase that can regulate DSB repair via the Ring finger protein8-Ring finger protein168(RNF8-RNF168) pathway. These findings suggest that an additional copy of genes on human chromosome21can selectively impair the ability of HSCs to repair DSBs, which may contribute to DS-associated hematological abnormalities and malignancies.
研究表明非整倍体可能降低DNA损伤修复功能,引起基因组的不稳定性。唐氏综合症相关的造血系统异常和恶性肿瘤可能与造血干细胞(HSCs)自我更新能力受损,造血系统基因不稳定有关,为此我们利用唐氏综合症模型小鼠对Ts65Dn小鼠造血干细胞数量、功能及辐射诱导DNA损伤修复机制进行研究。研究发现与野生型对照小鼠(Wild type,WT)相比,Ts65Dn小鼠的骨髓造血干细胞HSCs数量明显减少,造血祖细胞(HPCs)水平没有明显变化；体外单细胞克隆实验结果显示Ts65Dn小鼠HSCs单细胞克隆形成率明显低于对照小鼠,表明Ts65Dn小鼠骨髓HSC数量减少、功能下降。利用γH2AX表达检测Ts65Dn小鼠HSC/HPC损伤DNA双链断裂(DSB),发现Ts65Dn小鼠γH2AX表达水平高于对照小鼠；体外2Gyγ射线照射后1小时,两种小鼠的HSCs的DSB水平没有差异,但是随着时间延长,照射后3小时和6小时后Ts65Dn小鼠的HSCs的未修复的DSB水平显著高于对照组小鼠。且照射后Ts65Dn小鼠HSCs的克隆形成能力显著降低。与对照小鼠相比,Ts65Dn小鼠造血祖细胞体外克隆能力和DSB水平以及照射后DSB修复能力没有显著差异。结果提示Ts65Dn小鼠在HSC水平出现了DNA损伤修复障碍及功能损伤。
USP16基因编码一种去泛素化酶,Ts65Dn小鼠因多余的基因拷贝表达过高的,USP16基因,可能是造血干细胞DSB修复缺陷的重要分子机制。应用RT-PCR两个不同探针检测发现,与WT相比,Ts65Dn小鼠HPC内USP16表达分别升高1.45倍和1.53倍。而HSC内USP16表达分别升高2.21倍和2.04倍。由于Ts65Dn小鼠HSC中USP16过高表达会引起H2A和H2AX的过度去泛素化,干扰双链断裂位置修复蛋白乳腺癌1号基因(BRCA1)复合体,p53结合蛋白(53BP1)等分子的招募,这可能与Ts65Dn小鼠HSC出现DSB修复障碍有关。
综上,我们应用Ts65Dn小鼠作为唐氏综合症动物研究模型,发现Ts65Dn小鼠的造血干细胞出现数量和功能的异常,辐射敏感性增加；Ts65Dn小鼠HSC出现DSB修复障碍,可能与USP16在Ts65Dn小鼠HSC中高表达有关。DSB的正常修复是维持基因稳定性的重要因素。本项研究结果表明Ts65Dn小鼠造血干细胞DSB修复障碍可能是唐氏综合症病人早年造血系统异常以及白血病高发的原因之一。USP16有可能成为唐氏综合症治疗中的潜在靶点。
Down syndrome (DS) is the most common chromosomal abnormality in humans caused by the presence of all or part of a third copy of chromosome21. In addition to musculoskeletal and neurodevelopmental abnormalities, pediatric patients with DS also display various hematologic disorders and are at increased risk of acute lymphoblastic leukemia and acute megakaryocytic leukemia. Ts65Dn mice are trisomic for104orthologs of the genes on human chromosome21and are one of the most widely used mouse models for DS research, because they exhibit various deficiencies similar to DS patients. It has been shown that aneuploidy can impair DNA damage repair and induce genomic instability. Therefore, we investigated whether hematopoietic stem cells (HSCs) from Ts65Dn mice are deficient in the repair of DNA double-strand breaks (DSBs), because the deficiency in the repair of DSBs in HSCs can potentially contribute to DS-associated hematological abnormalities and malignancies by impairing HSC self-renewal and inducing hematopoietic genetic instability. Our results showed that Ts65Dn mice had significantly less bone marrow HSCs than wild-type (WT) littermate controls, whereas the levels of bone marrow hematopoietic progenitor cells (HPCs) were similar. The lower level of HSCs in Ts65Dn mice was associated with a significantly higher level of DSBs as determined by γH2AX staining and lower level of clonogenic activity in single cell cultures with SCF, TPO and FL3ligand when compared to the cells from WT controls. Although levels of DSBs in HSCs were similar at1hr after exposure to2Gy y-irradiation in vitro, HSCs from Ts65Dn mice had significantly higher levels of unrepaired DSBs than the cells from WT mice at3and6hr after irradiation. Moreover, after exposure to2Gy y-irradiation in vitro, the reduction in clonogenic function was significantly greater in Ts65Dn HSCs than WT HSCs. In contrast, no significant differences in these parameters were observed in HPCs from Ts65Dn and WT mice with or without irradiation.
The molecular mechanism by which extra copy of chromosome21causes HSC defect in repair of DSBs remains to be elucidated. It may be attributable to an increased expression of USP16in Ts65Dn HSCs, because USP16is a deubiquitinase that can regulate DSB repair via the Ring finger protein8-Ring finger protein168(RNF8-RNF168) pathway. These findings suggest that an additional copy of genes on human chromosome21can selectively impair the ability of HSCs to repair DSBs, which may contribute to DS-associated hematological abnormalities and malignancies.
引文
[1]. Ward OC. John Langdon Down:the man and the message[J]. Downs syndr Res Pract,1999,6(1):19-24.
[2]. Lejeune, J6rome; Gauthier Marie, Turpin R. Les chromosomes humains en culture de tissus[J]. CR Hebd Se'ances Acad Sci,1959, (248):602-603.
[3]. M6garban6 A, Ravel A, Mircher C, et al. The 50th anniversary of the discovery of trisomy 21:the past, present, and future of research and treatment of Down syndrome[J]. Genet Med,2009,11(9):611-616.
[4]. Gardiner, KJ. Molecular basis of pharmacotherapies for cognition in Down syndrome[J]. Trends Pharmacol Sci,2010,31(2):66-73.
[5]. de Graaf G, Haveman M, Hochstenbach R, et al. Changes in yearly birth prevalence rates of children with Down syndrome in the period 1986-2007 in The Netherlands[J]. J Intellect Disabil Res,2011,55(5):462-473.
[6]. Antonarakis SE, Lyle R, Dermitzakis ET, et al. Chromosome 21 and Down syndrome: from genomics to pathophysiology[J]. Nature Rev Genet,2004,5(10): 725-738.
[7]. Yang Q, Rasmussen SA, Friedman J M. Mortality associated with Down's syndrome in the USA from 1983 to 1997: a population-based study[J]. Lancet,2002, 359(9311):1019-1025.
[8]. Roth GM, Sun B, Greensite FS, et al. Premature aging in persons with Down syndrome: MR findings[J]. Am. J. Neuroradiol,1996,17(7):1283-1289.
[9]. Zigman WB, Lott IT. Alzheimer's disease in Down syndrome: neurobiology and risk[J]. Ment Retard Dev Disabil Res Rev,2007,13(3):237-246.
[10]. Izraeli S, Rainis L, Hertzberg L, et al. Trisomy of chromosome 21 in leukemogenesis[J]. Blood Cells Mol Dis,2007,39(2):156-159.
[11]. Kusters MA, Verstegen RH, Gemen EF, et al. In-trinsic defect of the immune system in children with Down syndrome: a review[J]. Clin Exp Immunol,2009, 156(2):189-193.
[12].Hasle H, Clemmensen IH, Mikkelsen M. Risks of leukaemia and solid tumours in individuals with Down's syndrome[J]. Lancet,2000,355(9199):165-169.
[13]. Whitlock JA, Sather HN, Gaynon P, et al. Clinical characteristics and outcome of children w ith Down syndrome and acute lymphoblastic leukemia: A Children's Cancer Group study[J]. Blood,2005,106(13):4043-4049.
[14]. Patrick K, Wade R, Goulden N, et al. Outcome of Down Syndrome associated Acute Lymphoblastic Leukaemia treated on a contemporary protocol[J]. British journal of haematology,2014.
[15]. Stefanidis K, Belitsos P, Fotinos A, et al. Causes of infertility in men with Down syndrome[J]. Andrologia,2011,43(5):353-357.
[16]. Manila Kaushal, Asha Baxi, Pooja Kadi, et al. Woman with Down Syndrome delivered a Normal Child[J]. International Journal of Infertility and Fetal Medicine, 2010,1(1):45-47.
[17]. Su X, Lau J T F, Yu C M, et al. Growth charts for Chinese Down syndrome children from birth to 14 years[J], Archives of Disease in Childhood,2014: archdischild-2013-304494.
[18]. Glasson, E.J., Sullivan, S.G., Hussain, R., Petterson, B.A., Montgomery,P.D. and Bittles, A.H. The changing survival profile of peoplewith Down's syndrome: implications for genetic counselling[J].Clin.Genet.,2002,62,390-393.
[19]. Underwood E. Can Down Syndrom Be Treated[J]. Science,2014,343(6174): 964-967.
[20]. Belichenko NP, Belichenko PV, Kleschevnikov AM, et al. The'Down syndrome critical region' is sufficient in the mouse model to confer behavioral, neurophysiological, and synaptic phenotypes characteristic of Down syndrome[J]. J Neurosci,2009,29(18):5938-5948.
[21]. Villar AJ, Belichenko PV, Gillespie AM, et al. Identification and characterization of a new Down syndrome model, Ts[Rb(12.1716)]2Cje, resulting from a spontaneous Robertsonian fusion between T(1716)65Dn and mouse chromosome 12[J]. Mamm Genome,2005,16(2):79-90.
[22]. Olson LE, Tien J, South S, et al. Long-range chromosomal engineering is more efficient in vitro than in vivo[J]. Transgenic Res,2005,14(3):325-332.
[23]. Davisson MT, Schmidt C, Akeson EC. Segmental trisomy of murine chromosome 16:a new model system for studying Down syndrome[J]. Prog Clin Biol Res,1990, 360:263-280.
[24]. Sago H, Carlson EJ, Smith DJ et al. TslCje, a partial trisomy 16 mouse model for Down syndrome, exhibits learning and behavioral abnormalities[J]. Proc Natl Acad Sci USA,1998,95(11):6256-6261.
[25]. Yamakawa, K. Towards the understanding of Down syndrome using mouse models. Congenit Anom(Kyoto).2012,52(2):67-71.
[26]. Kirsammer G, Jilani S, Liu H, et al. Highly penetrant myeloproliferative disease in the Ts65Dn mouse model of Down syndrome[J]. Blood,2008,111(2):767-775.
[27].Nikolaev S I, Santoni F, Vannier A, et al. Exome sequencing identifies putative drivers of progression of transient myeloproliferative disorder to AMKL in infants with Down syndrome[J]. Blood,2013,122(4):554-561.
[28]. Steele A, Scerif G, Cornish K, et al. Learning to read in Williams syndrome and Down syndrome: syndrome - specific precursors and developmental trajectories[J]. Journal of Child Psychology and Psychiatry,2013,54(7):754-762.
[29]. Yoshida K, Toki T, Park M, et al. Genetic basis of myeloid leukemogenesis in Down syndrome[C]//CANCER RESEARCH.615 CHESTNUT ST,17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA:AMER ASSOC CANCER RESEARCH, 2013,73(8).
[30]. Visootsak J, Hess B, Bakeman R, et al. Effect of congenital heart defects on language development in toddlers with Down syndrome[J]. Journal of Intellectual Disability Research,2013,57(9):887-892.
[31]. Zampieri B L, Fernandez F, Pearson J N, et al. Ultrasonic vocalizations during male-female interaction in the mouse model of Down syndrome Ts65Dn[J]. Physiology & behavior,2014,128:119-125.
[32]. Reeves RH, Baxter LL, Richtsmeier JT. Too much of a good thing:mechanisms of gene action in Down syndrome[J]. Trends Genet,2001,17(2):83-88.
[33]. Korenberg JR, Kawashima H, Pulst SM, et al. Molecular definition of a region of chromosome 21 that causes features of the Down syndrome phenotype[J]. Am J Hum Genet,1990,47 (2):236-246.
[34]. Olson LE, Richtsmeier JT, Leszl J, et al. A chromosome 21 critical region does not cause specific Down syndrome phenotypes[J]. Science,2004,06(5696):687-690.
[35]. Wang X, Zhao Y J, Zhang X F, et al. Loss of sorting nexin 27 contributes to excitatory synaptic dysfunction by modulating glutamate receptor recycling in Down's syndrome[J]. Nature Medicine,2013,19(4):473-480.
[36]. American Society of Human Genetics. "Gene-silencing strategy opens new path to understanding Down Syndrome." ScienceDaily. ScienceDaily,22 October 2013. www. sciencedaily.com/releases/2013/10/131022170726.htm.
[37]. Slonim DK, Koide K, Johnson KL, et al. Functional genomic analysis of amniotic fluid cell-free mRNA suggests that oxidative stress is significant in Down syndrome fetuses[J]. Proc Natl Acad Sci USA,2009,106(23):9425-9429.
[38]. Jovanovic SV, Clements D, MacLeod K. Biomarkers of oxidative stress are significantly elevated in Down syndrome[J]. Free Radic Biol Med,1998,25(9): 1044-1048.
[39]. Micali N, Longobardi E, Iotti G, et al. Down syndrome fibroblasts and mouse Prep1-overexpressing cells display increased sensitivity to genotoxic stress[J]. Nucleic Acids Res,2010,38(11):3595-3604.
[40]. Gimeno A, Garcia-Gim6nez J L, Audi L, et al. Decreased cell proliferation and higher oxidative stress in fibroblasts from Down Syndrome fetuses. Preliminary study[J]. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease,2014, 1842(1):116-125.
[41]. Bender CF, Sikes ML, Sullivan R, et al. Cancer predisposition and hematopoietic failure in Rad50(S/S) mice[J]. Genes Dev,2002,16(17):2237-2251.
[42].Nijnik A, Woodbine L, Marchetti C, et al. DNA repair is limiting for haematopoietic stem cells during ageing[J]. Nature,2007,447(7145):686-690.
[43]. Prasher JM, Lalai AS, Heijmans-Antonissen C, et al. Reduced hematopoietic reserves in DNA interstrand crosslinkrepair-deficient Erccl-/- mice[J]. EMBO J, 2005,24(4):861-871.
[44]. Rossi DJ, Bryder D, Seita J, et al. Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age[J]. Nature,2007,447(7145): 725-729.
[45]. Natarajan AT. Radiosensitivity of Cells Derived From Down Syndrome Patients: Is Defective DNA Repair Involved?[A]. In: Baljee AS. DNA Repair and Human Disease[M]. Springer US.
[46]. Chudina AP, Malyutina TS, Progosyane HE. Comparative radiosensitivity of chromosomes in the cultured peripheral blood lymphocytes of normal donors and patients with Down's syndrome[J]. Genetika,1966,4:51-63.
[47].Dekaban ASR, Thron R, Streusing JK. Chromosomal aberrations in irradiated blood and blood cultures of normal subjects and selected patients with chromosomal abnormality[J]. Radiat Res,1966,27(1):50-63.
[48]. Cherry LM, Shukla P, Atwell L. Age, gender, and sensitivity to bleomycin-induced chomosome breakage in Down's syndrome and control populations[J]. Cytobios, 1994,78(312):23-31.
[49]. Ravindran Ankathil, P Kusumakumary, M. Krishnan Nair. Increased Levels of Mutagen-Induced Chromosome Breakage in Down Syndrome Children with Malignancy[J]. Cancer Genet Cytogenet,1997,99(2):126-128.
[50]. Aldenhoff P, Wegner RD, Sperling K. Different sensitivity of diploid and trisomic cells from patients with Down syndrome mosaic after treatment with the trifunctional alkylating agent trenimon[J]. Hum Genet,1980,56(1):123-125.
[51]. Makoto Higurash, Aiko Tada, Shinobu Miyahara, et al. Chromosome Damage in Down's Syndrome Induced by Chickenpox Infection[J]. Pediatric Research,1976, 10(3):189-192.
[52]. Athanasiou K, Sideris EG, Bartsocas C. Decreased repair of X-ray induced DNA single strand breaks in lymphocytes in Down's syndrome[J]. Padiatr Res,1980, 14(4 Pt 1):336-338.
[53]. Lenard JC, Mertz T. Repair of single strand breaks in normal and trisomic lymphocytes[J]. Mutation Res,1982,105(6):417-422.
[54]. Steiner ME, Woods WG. Normal formation and repair of γ-radiation-induced single and double strand DNA breaks in Down syndrome fibroblasts[J]. Mutation Res,1982,95(2-3):515-523.
[55]. Raji NS, Rao KS. Trisomy 21 and accelerated aging: DNA-repair parameters in peripheral lymphocytes of Down's syndrome patients[J]. Mech Ageing Dev,1988, 100(1):85-101.
[56]. Druzhyna N, Nair RG, Ledoux SP, et al. Defective repair of oxidative damage in mitochondrial DNA in Down's syndrome[J]. Mutat Res,1998,409(2):81-89.
[57].Zana M, Sz6cs6nyi A, Czibula A, et al. Age-dependent oxidative stress-induced DNA damage in Down's lymphocytes[J]. Biochem Biophys Res Commun,2006, 345(2):726-733.
[58]. Joo HY, Zhai L, Yang C, et al. Regulation of cell cycle progression and gene expression by H2A deubiquitylation[J]. Nature,2007,449(7165):1068-1072.
[59]. Adorno M, Sikandar S, Mitra SS, et al. Usp16 contributes to somatic stem-cell defects in Down's syndrome[J]. Nature,2013,501(7467):380-384.
[60]. Cuadrado E, Barrena MJ. Immune dysfunction in Down's syndrome: primary immune deficiency or early senescence of the immune system? [J]. Clin Immunol Immunopathol,1996,78(3),209-214.
[61].Mundschau G, Gurbuxani S, Gamis AS, et al. Mutagenesis of GATA1 is an initiating event in Down syndrome leukemogenesis[J]. Blood,2003,101(11): 4298-4300.
[62]. Wechsler J, Greene M, McDevitt MA, et al. Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome[J]. Nat Genet,2002,32(1): 148-152.
[63]. Hitzler JK, Cheung J, Li Y, et al. GATA1 mutations in transient leukemia and acute megakaryoblastic leukemia of Down syndrome[J]. Blood,2003,101(11):4301-4304.
[64]. Alford KA, Reinhardt K, Garnett C, et al. Analysis of GATA1 mutations in Down syndrome TMD and myeloid leukemia[J]. Blood,2011,118(8):2222-2238.
[65]. Russell LJ, Capasso M, Vater L et al. Deregulated expression of cytokine receptor gene, CRLF2, is involved in lymphoid transformation in B-cell precursor acute lymphoblastic leukemia[J]. Blood,2009,114(13):2688-2698.
[66]. Spangrude GJ, Heimfeld S, Weissman IL. Purification and characterization of mouse hematopoietic stem cells[J]. Science,1988,241(4861):58-62.
[67]. Ogawa M, Matsuzaki Y, Nishikawa S, et al. Expression and function of c-kit in hemopoietic progenitor cells[J]. J Exp Med,1991,174(1):63-71.
[68]. Osawa M, Hanada K, Hamada H, Nakauchi H. Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell[J]. Science, 1996,273(5272):242-245.
[69]. Christensen JL, Weissman IL. Flk-2 is a marker in hematopoietic stem cell differentiation: a simple method to isolate long-term stem cells[J]. Proc Natl Acad Sci USA.
[70]. Kiel MJ, Yilmaz OH, Iwashita T, et al. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells[J]. Cell,2005,121(7):1109-1121.
[71]. Ito K, Hirao A, Arai F, et al. Re-active oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells[J]. Nat Med,2006,12(4):446-451.
[72]. Tothova Z, Kollipara R, Huntly BJ, et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress[J]. Cell,2007, 128(2):325-339.
[73], Shao L, Li H, Pazhanisamy SK, et al. Reactive oxygen species and hematopoietic stem cell senescence[J]. Int J Hematol,2011,94(1):24-32.
[74]. Lorenzo LP, Chen H, Shatynski KE, et al. Defective hematopoietic stem cell and lymphoid progenitor development in the Ts65Dn mouse model of Down syndrome: potential role of oxidative stress[J]. Antioxid Redox Signal,2011,15(8):2083-2094.
[75]. Cheshier SH, Morrison SJ, Liao X, et al. In vivo proliferation and cell cycle kinetics of long-term self-renewing hematopoietic stem cells[J]. Proc Natl Acad Sci USA, 1999,96(6):3120-3125.
[76]. Behar TN, Colton CA. Redox regulation of neuronal migration in a Down Syndrome model[J]. Free Radic Biol Med,2003,35(6):566-575.
[77]. Yamamoto H, Tang H. Melatonin attenuates L-cysteine-induced seizures and lipid peroxidation in the brain of mice[J]. J Pineal Res,1996,21(2):108-113.
[78]. Yamamoto H. Preventive effect of N(G)-nitro-L-arginine against L-cysteine-induced seizures in mice[J]. Toxicol Lett,1996,84(1):1-5.
[79], Hershkovitz E, Shorer Z, Levitas A, et al. Status epilepticus following intravenous N-acetylcysteine therapy [J]. Isr J Med Sci,1996,32(11):1102-1104.
[80].Blake CCF, Phillips DC. Effects of X-irradiation on single crystals of myoglobin[A]. in proceedings of a symposium held at Brno. Biological Effects of Ionizing Radiation at the Molecular Level, proceedings of a symposium held at Brno[[C]. Vienna:International Atomic Energy Agency.1962:183-191.
[81]. Haber JE. Partners and pathways repairing a double-strand break[J]. Trends Genet, 2000,16 (6):259-264.
[82]. Lieber MR. The mechanism of human nonhomologous DNA end joining[J]. J Biol Chem,2008,283 (1):1-5.
[83]. Sonoda E, Hochegger H, Saberi A, et al. Differential usage of non-homologous end-joining and homologous recombination in double strand break repair[J]. DNA Repair (Amst),2006,5 (9-10):1021-1029.
[84]. Shrivastav M, De Haro LP, Nickoloff JA. Regulation of DNA double-strand break repair pathway choice[J]. Cell Res,2008,18 (1):134-147.
[85]. Mohrin M, Bourke E, Alexander D, et al. Hematopoietic stem cell quiescence promotes error prone DNA repair and mutagenesis[J]. Cell Stem Cell,2010,7(2): 174-185.
[86]. West MH, Bonner WM. Histone 2A, a heteromorphous family of eight protein species[J]. Biochemistry,1980,19 (14):3238-3245.
[87]. Rogakou EP, Pilch DR, Orr AH, et al. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139[J]. J Biol Chem,1998,273 (10):5858-5868.
[88]. Rothkamm K, Horn S. Gamma-H2AX as protein biomarker for radiation exposure[J]. Ann 1st Super Sanita,2009,45 (3):265-271.
[89]. Redon CE, Dickey JS, Bonner WM, et al. Gamma-H2AX as a biomarker of DNA damage induced by ionizing radiation in human peripheral blood lymphocytes and artificial skin[J]. Adv Space Res,2009,43 (8):1171-1178.
[90]. Shanbhag NM, Rafalska-Metcalf IU, Balane-Bolivar C, et al. ATM-dependent chromatin changes silence transcription in cis to DNA double-strand breaks[J]. Cell, 2010,141(6):970-981.
[91].Mattiroli F, Vissers JH, van Dijk WJ, et al. RNF168 ubiquitinates K13-15 on H2A/H2AX to drive DNA damage signaling[J]. Cell,2012,150(6):1182-1195.
[92]. Uhrhammer NA, Lafarge L, Dos Santos L, et al. Werner syndrome and mutations of the WRN and LMNA genes in France[J]. Hum Mutat,2006,27(7):718-719.
[93]. Moser MJ, Oshima J, Monnat RJ Jr. WRN mutations in Werner syndrome[J]. Hum Mutat,1999,13(4):271-270.
[94]. Kusumoto-Matsuo R, Ghosh D, Karmakar P, et al. Serines 440 and 467 in the Werner syndrome protein are phosphorylated by DNA-PK and affects its dynamics in response to DNA double strand breaks[J]. Aging(Albany NY),2014,6(l):70-81.
[95]. li B, lglesias-Pedraz JM, Chen LY, et al. Downregulation of the Werner syndrome protein induces a metabolic shift that compromises redox homeostasis and limits proliferation of cancer cells. Aging cell,2014,13(2):367-378.
[96].Arora H, Chacon AH, Choudhary S, et al. Bloom syndrome[J]. Int J Dermatol,2014, doi.10.1111/ijd.12408. [Epub ahead of print].
[97]. Salah GB, Salem IH, masmoudi A, et al. Chromosomal instability associated with a novel BLM frameshift mutation (c.1980-1982delAA) in two unrelated Tunisian families with Bloom syndrome[J]. J Eur Acad Dermatol Venereol,2013, doi: 10.1111/jdv.12279. [Epub ahead of print].
[98]. Grabarz A, Guiouilh-Barbat J, Barascu A. et al. A role for BLM in double-strand break repair pathway choice: prevention of CtlP/Mrel1-mediated alternative nonhomologous end-joining[J]. Cell Rep,2013,5(1):21-28.
[99]. Hisata S, Sakaguchi H, Kanegane H, et al. A Novel Missense Mutation of DKC1 in Dyskeratosis Congenita With Pulmonary Fibrosis[J]. Sarcoidosis Vasc Diffuse Lung Dis,2013,30(3):221-225.
[100]. Kirwan M, Beswick R, Vulliamy T, et al. Exogenous TERC alone can enhance proliferative potential, telomerase activity and telomere length in lymphocytes from dyskeratosis congenita patients[J]. Br J Haematol,2009,144(5):771-781.
[101]. Gourronc FA, Robertson mM, herrig AK, et al. Proliferative defects in dyskeratosis congenita skin keratinocytes are corrected by expression of the telomerase reverse transcriptase, TERT, or by activation of endogenous telomerase through expression of papillomavirus E6/E7 or the telomerase RNA component, TERC[J]. Exp Dermatol,2010,19(3):279-288.
[102]. O'Connell N, Goodyer M, Gleeson M, et al. Successful treatment with rituximab and mycophenolate mofetil of refractory autoimmune hemolytic anemia post-hematopoietic stem cell transplant for dyskeratosis congenita due to TINF2 mutation[J]. Pediatr Transplant,2014,18(1):E22-24.
[103]. Pereboeva L, Westin E, Patel T, et al. DNA damage responses and oxidative stress in dyskeratosis congenita[J]. PLoS One,2013,8(10):e76473.
[104]. Sheltzer JM, Blank HM, Pfau SJ, et al. Aneuploidy drives genomic instability in yeast[J]. Science,2011,333(6045):1026-1030.
[105]. Aaltonen LA, Peltomaki P, Leach FS, et al. Clues to the pathogenesis of familial colorectal cancer[J]. Science,1993,260(5109):812-816.
[106]. Watatani M, Yoshida T, Kuroda K, et al. Allelic loss of chromosome 17p, mutation of the p53 gene, and microsatellite instability in right- and left-sided colorectal cancer[J]. Cancer,1996,77(8):1688-1693.
[107]. Hershko A, Ciechanover A. The ubiquitin system[J]. Annual Review of Biochemistry,1998,67:425-479.
[108]. Clague MJ, Urb6 S. Ubiquitin: same molecule, different degradation pathways[J]. Cell,2010,143(5):682-685.
[109]. Neutzner M, Neutzner A. Enzymes of ubiquitination and deubiquitination[J]. EssaysBiochem,2012,52(1):37-50.
[110]. Varshavsky A. The ubiquitin system, an immense realm[J]. Annu Rev Biochem, 2012,81:167-176.
[111]. Komander D, Rape M. The ubiquitin code[J]. Annu Rev Biochem,2012,81: 203-229.
[112]. Adorno M, Sikandar S, Mitra SS, et al, Usp16 contributes to somatic stem-cell defects in Down's syndrome. Nature,2013:p.501(7467):7380-7384.
[113]. Ciccia A, Elledge SJ. The DNA damage response: Making it safe to play with knives[J]. Molecular Cell,2010,40(2):179-204.
[114]. Jackson SP, Bartek J. The DNA-damage response in human biology and disease[J]. Nature,2009,461(7267):1071-1078.
[115]. Branzei D, Foiani M. Regulation of DNA repair throughout the cell cycle[J]. Nat Rev Mol Cell Biol,2008,9(4):297-308.
[1]. Souroullas G P, Sharpless N E. Stem cells: Down's syndrome link to ageing[J]. Nature,2013,501(7467):325-326.
[2]. Ward OC. John Langdon Down:the man and the message[J]. Downs syndr Res Pract,1999,6(1):19-24.
[3]. Megarbane A, Ravel A, Mrcher C, et al. The 50th anniversary of the discovery of trisomy 21:the past, present, and future of research and treatment of Down syndrome[J]. Genet Med,2009,11(9):611-616.
[4]. Gardiner, KJ. Molecular basis of pharmacotherapies for cognition in Down syndrome[J]. Trends Pharmacol Sci,2010,31(2):66-73.
[5]. de Graaf G, Haveman M, Hochstenbach R, et al. Changes in yearly birth prevalence rates of children with Down syndrome in the period 1986-2007 in The Netherlands[J]. J Intellect Disabil Res,2011,55(5):462-473.
[6]. Antonarakis SE, Lyle R, Dermitzakis ET, et al. Chromosome 21 and Down syndrome: from genomics to pathophysiology[J]. Nature Rev Genet,2004,5(10): 725-738.
[7]. Yang Q, Rasmussen SA, Friedman J M. Mortality associated with Down's syndrome in the USA from 1983 to 1997:a population-based study[J]. Lancet,2002, 359(9311):1019-1025.
[8]. Roth GM, Sun B, Greensite FS, et al. Premature aging in persons with Down syndrome: MR findings[J]. Am. J. Neuroradiol,1996,17(7):1283-1289.
[9]. Zigman WB, Lott IT. Alzheimer's disease in Down syndrome: neurobiology and risk[J]. Ment Retard Dev Disabil Res Rev,2007,13(3):237-246.
[10]. Izraeli S, Rainis L, Hertzberg L, et al. Trisomy of chromosome 21 in leukemogenesis[J]. Blood Cells Mol Dis,2007,39(2):156-159.
[11]. Kusters MA, Verstegen RH, Gemen EF, et al. In-trinsic defect of the immune system in children with Down syndrome: a review[J]. Clin Exp Immunol,2009, 156(2):189-193.
[12]. Hasle H, Clemmensen IH, Mikkelsen M. Risks of leukaemia and solid tumours in individuals with Down's syndrome[J]. Lancet,2000,355(9199):165-169.
[13]. Whitlock JA, Sather HN, Gaynon P, et al. Clinical characteristics and outcome of children w ith Down syndrome and acute lymphoblastic leukemia: A Children's Cancer Group study[J]. Blood,2005,106(13):4043-4049.
[14]. Stefanidis K, Belitsos P, Fotinos A, et al. Causes of infertility in men with Down syndrome[J]. Andrologia,2011,43(5):353-357.
[15].Manila Kaushal, Asha Baxi, Pooja Kadi, et al. Woman with Down Syndrome delivered a Normal Child[J]. International Journal of Infertility and Fetal Medicine, 2010,1(1):45-47.
[16]. Glasson, E.J., Sullivan, S.G., Hussain, R., Petterson, B.A., Montgomery,P.D. and Bittles, A.H. The changing survival profile of peoplewith Down's syndrome: implications for genetic counselling[J].Clin.Genet.,2002,62,390-393.
[17]. Cuadrado E, Barrena MJ. Immune dysfunction in Down's syndrome: primary immune deficiency or early senescence of the immune system? [J]. Clin Immunol Immunopathol,1996,78(3),209-214.
[18].Mundschau G, Gurbuxani S, Gamis AS, et al. Mutagenesis of GATA1 is an initiating event in Down syndrome leukemogenesis[J]. Blood,2003,101(11): 4298-4300.
[19]. Spangrude GJ, Heimfeld S, Weissman IL. Purification and characterization of mouse hematopoietic stem cells[J]. Science,1988,241(4861):58-62.
[20]. Ogawa M, Matsuzaki Y, Nishikawa S, et al. Expression and function of c-kit in hemopoietic progenitor cells[J]. J Exp Med,1991,174(1):63-71.
[21]. Osawa M, Hanada K, Hamada H, Nakauchi H. Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell[J]. Science, 1996,273(5272):242-245.
[22]. Christensen JL, Weissman IL. Flk-2 is a marker in hematopoietic stem cell differentiation: a simple method to isolate long-term stem cells[J]. Proc Natl Acad Sci USA.
[23].Kiel MJ, Yilmaz OH, Iwashita T, et al. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells[J]. Cell,2005,121(7):1109-1121.
[24]. Belichenko NP, Belichenko PV, Kleschevnikov AM, et al. The 'Down syndrome critical region1 is sufficient in the mouse model to confer behavioral, neurophysiological, and synaptic phenotypes characteristic of Down syndrome[J]. J Neurosci,2009,29(18):5938-5948.
[25].Davisson MT, Schmidt C, Akeson EC. Segmental trisomy of murine chromosome 16:a new model system for studying Down syndrome[J]. Prog Clin Biol Res,1990, 360:263-280.
[26]. Sago H, Carlson EJ, Smith DJ et al. Ts1Cje, a partial trisomy 16 mouse model for Down syndrome, exhibits learning and behavioral abnormalities[J]. Proc Natl Acad Sci USA,1998,95(11); 6256-6261.
[27]. Villar AJ, Belichenko PV, Gillespie AM, et al. Identification and characterization of a new Down syndrome model, Ts[Rb(12.1716)]2Cje, resulting from a spontaneous Robertsonian fusion between T(1716)65Dn and mouse chromosome 12[J]. Mamm Genome,2005,16(2):79-90.
[28]. Olson LE, Tien J, South S, et al. Long-range chromosomal engineering is more efficient in vitro than in vivo[J]. Transgenic Res,2005,14(3):325-332.
[29]. Yamakawa, K. Towards the understanding of Down syndrome using mouse models. Congenit Anom(Kyoto).2012,52(2):67-71.
[30]. Zampieri B L, Fernandez F, Pearson J N, et al. Ultrasonic vocalizations during male-female interaction in the mouse model of Down syndrome Ts65Dn[J]. Physiology & behavior,2014,128:119-125.
[31]. Visootsak J, Hess B, Bakeman R, et al. Effect of congenital heart defects on language development in toddlers with Down syndrome[J]. Journal of Intellectual Disability Research,2013,57(9):887-892.
[32]. Kirsammer G, Jilani S, Liu H, et al. Highly penetrant myeloproliferative disease in the Ts65Dn mouse model of Down syndrome[J]. Blood,2008,111(2):767-775.
[33]. Wechsler J, Greene M, McDevitt MA, et al. Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome[J]. Nat Genet,2002,32(1): 148-152.
[34]. Hitzler JK, Cheung J, Li Y, et al. GATA1 mutations in transient leukemia and acute megakaryoblastic leukemia of Down syndrome[J]. Blood,2003,101(11):4301-4304.
[35]. Alford KA, Reinhardt K, Garnett C, et al. Analysis of GATA1 mutations in Down syndrome TMD and myeloid leukemia[J]. Blood,2011,118(8):2222-2238.
[36]. Russell LJ, Capasso M, Vater I, et al. Deregulated expression of cytokine receptor gene, CRLF2, is involved in lymphoid transformation in B-cell precursor acute lymphoblastic leukemia[J]. Blood,2009,114(13):2688-2698.
[37]. Lorenzo LP, Chen H, Shatynski KE, et al. Defective hematopoietic stem cell and lymphoid progenitor development in the Ts65Dn mouse model of Down syndrome: potential role of oxidative stress[J]. Antioxid Redox Signal,2011,15(8):2083-2094.
[38]. Reeves RH, Baxter LL, Richtsmeier JT. Too much of a good thing:mechanisms of gene action in Down syndrome[J]. Trends Genet,2001,17(2):83-88.
[39]. Korenberg JR, Kawashima H, Pulst SM, et al. Molecular definition of a region of chromosome 21 that causes features of the Down syndrome phenotype[J]. Am J Hum Genet,1990,47 (2):236-246.
[40]. Olson LE, Richtsmeier JT, Leszl J, et al. A chromosome 21 critical region does not cause specific Down syndrome phenotypes[J]. Science,2004,06(5696):687-690.
[41]. Slonim DK, Koide K, Johnson KL, et al. Functional genomic analysis of amniotic fluid cell-free mRNA suggests that oxidative stress is significant in Down syndrome fetuses[J]. Proc Natl Acad Sci USA,2009,106(23):9425-9429.
[42]. Ito K, Hirao A, Arai F, et al. Re-active oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells[J]. Nat Med,2006,12(4):446-451.
[43]. Tothova Z, Kollipara R, Huntly BJ, et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress[J]. Cell,2007, 128(2):325-339.
[44]. Shao L, Li H, Pazhanisamy SK, et al. Reactive oxygen species and hematopoietic stem cell senescence[J]. Int J Hematol,2011,94(1):24-32.
[45].Behar TN, Colton CA. Redox regulation of neuronal migration in a Down Syndrome model[J]. Free Radic Biol Med,2003,35(6).566-575.
[46], Yamamoto H, Tang H. Melatonin attenuates L-cysteine-induced seizures and lipid peroxidation in the brain of mice[J]. J Pineal Res,1996,21(2):108-113.
[47]. Yamamoto H. Preventive effect of N(G)-nitro-L-arginine against L-cysteine-induced seizures in mice[J]. Toxicol Lett,1996,84(1):1-5.
[48]. Hershkovitz E, Shorer Z, Levitas A, et al. Status epilepticus following intravenous N-acetylcysteine therapy[J]. Isr J Med Sci,1996,32(11):1102-1104.
[49].Blake CCF, Phillips DC. Effects of X-irradiation on single crystals of myoglobin[A]. in proceedings of a symposium held at Brno. Biological Effects of Ionizing Radiation at the Molecular Level, proceedings of a symposium held at Brno[[C]. Vienna: International Atomic Energy Agency.1962:183-191.
[50]. Haber JE. Partners and pathways repairing a double-strand break[J]. Trends Genet, 2000,16 (6):259-264.
[51]. Lieber MR. The mechanism of human nonhomologous DNA end joining[J]. J Biol Chem,2008,283(1):1-5.
[52]. Sonoda E, Hochegger H, Saberi A, et al. Differential usage of non-homologous end-joining and homologous recombination in double strand break repair[J]. DNA Repair (Amst.),2006,5 (9-10):1021-1029.
[53]. Shrivastav M, De Haro LP, Nickoloff JA. Regulation of DNA double-strand break repair pathway choice[J]. Cell Res,2008,18 (1):134-147.
[54]. Mohrin M, Bourke E, Alexander D, et al. Hematopoietic stem cell quiescence promotes error prone DNA repair and mutagenesis[J]. Cell Stem Cell,2010,7(2): 174-185.
[55]. Bender CF, Sikes ML, Sullivan R, et al. Cancer predisposition and hematopoietic failure in Rad50(S/S) mice[J]. Genes Dev,2002,16(17):2237-2251.
[56]. Nijnik A, Woodbine L, Marchetti C, et al. DNA repair is limiting for haematopoietic stem cells during ageing[J]. Nature,2007,447(7145):686-690.
[57]. Prasher JM, Lalai AS, Heijmans-Antonissen C, et al. Reduced hematopoietic reserves in DNA interstrand crosslinkrepair-deficient Erccl-/- mice[J]. EMBO J, 2005,24(4):861-871.
[58]. Rossi DJ, Bryder D, Seita J, et al. Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age[J]. Nature,2007,447(7145): 725-729.
[59].Natarajan AT. Radiosensitivity of Cells Derived From Down Syndrome Patients:Is Defective DNA Repair Involved?[A]. In: Baljee AS. DNA Repair and Human Disease[M]. Springer US.
[60]. Chudina AP, Malyutina TS, Progosyane HE. Comparative radiosensitivity of chromosomes in the cultured peripheral blood lymphocytes of normal donors and patients with Down's syndrome[J]. Genetika,1966,4:51-63.
[61]. Dekaban ASR, Thron R, Streusing JK. Chromosomal aberrations in irradiated blood and blood cultures of normal subjects and selected patients with chromosomal abnormality [J]. Radiat Res,1966,27(1):50-63.
[62]. Cherry LM, Shukla P, Atwell L. Age, gender, and sensitivity to bleomycin-induced chomosome breakage in Down's syndrome and control populations[J]. Cytobios, 1994,78(312):23-31.
[63]. Ravindran Ankathil, P Kusumakumary, M. Krishnan Nair. Increased Levels of Mutagen-Induced Chromosome Breakage in Down Syndrome Children with Malignancy[J]. Cancer Genet Cytogenet,1997,99(2):126-128.
[64]. Aldenhoff P, Wegner RD, Sperling K. Different sensitivity of diploid and trisomic cells from patients with Down syndrome mosaic after treatment with the trifunctional alkylating agent trenimon[J]. Hum Genet,1980,56(1):123-125.
[65]. Makoto Higurash, Aiko Tada, Shinobu Miyahara, et al. Chromosome Damage in Down's Syndrome Induced by Chickenpox Infection[J]. Pediatric Research,1976, 10(3):189-192.
[66]. Athanasiou K, Sideris EG, Bartsocas C. Decreased repair of X-ray induced DNA single strand breaks in lymphocytes in Down's syndrome[J]. Padiatr Res,1980, 14(4 Pt 1):336-338.
[67]. Lenard JC, Mertz T. Repair of single strand breaks in normal and trisomic lymphocytes[J]. Mutation Res,1982,105(6):417-422.
[68]. Steiner ME, Woods WG. Normal formation and repair of y-radiation-induced single and double strand DNA breaks in Down syndrome fibroblasts[J]. Mutation Res, 1982,95(2-3):515-523.
[69]. Raji NS, Rao KS. Trisomy 21 and accelerated aging: DNA-repair parameters in peripheral lymphocytes of Down's syndrome patients[J]. Mech Ageing Dev,1988, 100(1):85-101.
[70]. Druzhyna N, Nair RG, Ledoux SP, et al. Defective repair of oxidative damage in mitochondrial DNA in Down's syndrome[J]. Mutat Res,1998,409(2):81-89.
[71].Zana M, Szecsenyi A, Czibula A, et al. Age-dependent oxidative stress-induced DNA damage in Down's lymphocytes[J]. Biochem Biophys Res Commun,2006, 345(2):726-733.
[72]. Hershko A, Ciechanover A. The ubiquitin system[J]. Annual Review of Biochemistry,1998,67:425-479.
[73]. Clague MJ, Urbe S. Ubiquitin: same molecule, different degradation pathways[J]. Cell,2010,143(5):682-685.
[74].Neutzner M, Neutzner A. Enzymes of ubiquitination and deubiquitination[J]. EssaysBiochem,2012,52(1):37-50.
[75]. Varshavsky A. The ubiquitin system, an immense realm[J]. Annu Rev Biochem, 2012,81:167-176.
[76]. Komander D, Rape M. The ubiquitin code[J]. Annu Rev Biochem,2012,81: 203-229.
[77]. West MH, Bonner WM. Histone 2A, a heteromorphous family of eight protein species[J]. Biochemistry,1980,19 (14):3238-3245.
[78]. Rogakou EP, Pilch DR, Orr AH, et al. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139[J]. J Biol Chem,1998,273 (10):5858-5868.
[79]. Shanbhag NM, Rafalska-Metcalf IU, Balane-Bolivar C, et al. ATM-dependent chromatin changes silence transcription in cis to DNA double-strand breaks[J]. Cell, 2010,141(6):970-981.
[80]. Mattiroli F, Vissers JH, van Dijk WJ, et al. RNF168 ubiquitinates K13-15 on H2A/H2AX to drive DNA damage signaling[J]. Cell,2012,150(6):1182-1195.
[81]. Adorno M, Sikandar S, Mitra SS, et al, Usp16 contributes to somatic stem-cell defects in Down's syndrome. Nature,2013:p.501(7467):7380-7384.
[1]Hofer M, Pospisil M, Hoferova Z, et al. Stimulatory action of cyclooxygenase inhibitors on hematopoiesis: a review[J]. Molecules,2012,17(5):5615-5625.
[2]Gentile P, Byer D, Pelus LM. In vivo modulation of murine myelopoiesis following intravenous administration of prostaglandin E2[J]. Blood,1983,62(5):1100-1107.
[3]Pelus LM. Association between colony forming units-granulocyte macrophage expression of la-like (HLA-DR) antigen and control of granulocyte and macrophage production[J]. A new role for prostaglandin E. J Clin Invest,1982, 70(3):568-578.
[4]Pelus LM. Blockade of prostaglandin biosynthesis in intact mice dramatically augments the expansion of committed myeloid progenitor cells (colony-forming units-granulocyte, macrophage) after acute administration of recombinant human IL-1 alpha[J]. J Immunol,1989,143(12):4171-4179.
[5]Pelus LM, Hoggatt J, Singh P. Pulse exposure of haematopoietic grafts to prostaglandin E2 in vitro facilitates engraftment and recovery [J]. Cell Prolif,2011, 44 Suppl1:S22-29.
[6]Pelus LM, Hoggatt J. Pleiotropic effects of prostaglandin E2 in hematopoiesis; prostaglandin E2 and other eicosanoids regulate hematopoietic stem and progenitor cell function[J], Prostaglandins Other Lipid Mediat,2011,96(1-4):3-9.
[7]Hoggatt J, Singh P, Stilger KN, et al. Recovery from hematopoietic injury by modulating prostaglandin E(2) signaling post-irradiation[J]. Blood Cells Mol Dis, 2013,50(3):147-153.
[8]Ludin A, Itkin T, Gur-Cohen S, et al. Monocytes-macrophages that express a-smooth muscle actin preserve primitive hematopoietic cells in the bone marrow[J]. Nat Immunol,2012,13(11):1072-1082.
[9]Lord AM, North TE, Zon LI. Prostaglandin E2:making more of your marrow[J]. Cell Cycle,2007,6(24):3054-3057.
[10]Park JY, Pillinger MH, Abramson SB. Prostaglandin E2 synthesis and secretion: the role of PGE2 synthases[J]. Clin Immunol,2006,119(3):229-240.
[11]Murakami M, Kudo I. Prostaglandin E synthase: a novel drug target for inflammation and cancer[J]. Curr Pharm Des,2006,12(8):943-954.
[12]Rundhaug JE, Simper MS, Surh I, et al. The role of the EP receptors for prostaglandin E2 in skin and skin cancer[J]. Cancer Metastasis Rev,2011,30(3-4): 465-480.
[13]Hoggatt J, Singh P, Sampath J, et al. Prostaglandin E2 enhances hematopoietic stem cell homing, survival, and proliferation[J]. blood,2009,113(22):5444-5455.
[14]Zou YR, Kottmann AH, Kuroda M, et al. Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development J]. Nature,1998, 393(6685):595-599.
[15]Lorenz M, Slaughter HS, Wescott DM, et al. Cyclooxygenase-2 is essential for normal recovery from 5-fluorouracil-induced myelotoxicity in mice[J]. Exp Hematol,1999,27(10):1494-1502.
[16]North TE, Goessling W, Walkley CR, et al. Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis[J]. Nature,2007,447(7147): 1007-1011.
[17]Frisch BJ, Porter RL, Gigliotti BJ, et al. In vivo prostaglandin E2 treatment alters the bone marrow microenvironment and preferentially expands short-term hematopoietic stem cells[J]. Blood,2009,114(19):4054-4063.
[18]Goessling W, North TE, Loewer S, et al. Genetic interaction of PGE2 and Wnt signaling regulates developmental specification of stem cells and regeneration[J]. cell,2009,136(6):1136-1147.
[19]Goessling W, Allen RS, Guan X, et al. Prostaglandin E2 enhances human cord blood stem cell xenotransplants and shows long-term safety in preclinical nonhuman primate transplant models[J]. Cell Stem Cell,2011,8(4):445-458.
[2]. Lejeune, J6rome; Gauthier Marie, Turpin R. Les chromosomes humains en culture de tissus[J]. CR Hebd Se'ances Acad Sci,1959, (248):602-603.
[3]. M6garban6 A, Ravel A, Mircher C, et al. The 50th anniversary of the discovery of trisomy 21:the past, present, and future of research and treatment of Down syndrome[J]. Genet Med,2009,11(9):611-616.
[4]. Gardiner, KJ. Molecular basis of pharmacotherapies for cognition in Down syndrome[J]. Trends Pharmacol Sci,2010,31(2):66-73.
[5]. de Graaf G, Haveman M, Hochstenbach R, et al. Changes in yearly birth prevalence rates of children with Down syndrome in the period 1986-2007 in The Netherlands[J]. J Intellect Disabil Res,2011,55(5):462-473.
[6]. Antonarakis SE, Lyle R, Dermitzakis ET, et al. Chromosome 21 and Down syndrome: from genomics to pathophysiology[J]. Nature Rev Genet,2004,5(10): 725-738.
[7]. Yang Q, Rasmussen SA, Friedman J M. Mortality associated with Down's syndrome in the USA from 1983 to 1997: a population-based study[J]. Lancet,2002, 359(9311):1019-1025.
[8]. Roth GM, Sun B, Greensite FS, et al. Premature aging in persons with Down syndrome: MR findings[J]. Am. J. Neuroradiol,1996,17(7):1283-1289.
[9]. Zigman WB, Lott IT. Alzheimer's disease in Down syndrome: neurobiology and risk[J]. Ment Retard Dev Disabil Res Rev,2007,13(3):237-246.
[10]. Izraeli S, Rainis L, Hertzberg L, et al. Trisomy of chromosome 21 in leukemogenesis[J]. Blood Cells Mol Dis,2007,39(2):156-159.
[11]. Kusters MA, Verstegen RH, Gemen EF, et al. In-trinsic defect of the immune system in children with Down syndrome: a review[J]. Clin Exp Immunol,2009, 156(2):189-193.
[12].Hasle H, Clemmensen IH, Mikkelsen M. Risks of leukaemia and solid tumours in individuals with Down's syndrome[J]. Lancet,2000,355(9199):165-169.
[13]. Whitlock JA, Sather HN, Gaynon P, et al. Clinical characteristics and outcome of children w ith Down syndrome and acute lymphoblastic leukemia: A Children's Cancer Group study[J]. Blood,2005,106(13):4043-4049.
[14]. Patrick K, Wade R, Goulden N, et al. Outcome of Down Syndrome associated Acute Lymphoblastic Leukaemia treated on a contemporary protocol[J]. British journal of haematology,2014.
[15]. Stefanidis K, Belitsos P, Fotinos A, et al. Causes of infertility in men with Down syndrome[J]. Andrologia,2011,43(5):353-357.
[16]. Manila Kaushal, Asha Baxi, Pooja Kadi, et al. Woman with Down Syndrome delivered a Normal Child[J]. International Journal of Infertility and Fetal Medicine, 2010,1(1):45-47.
[17]. Su X, Lau J T F, Yu C M, et al. Growth charts for Chinese Down syndrome children from birth to 14 years[J], Archives of Disease in Childhood,2014: archdischild-2013-304494.
[18]. Glasson, E.J., Sullivan, S.G., Hussain, R., Petterson, B.A., Montgomery,P.D. and Bittles, A.H. The changing survival profile of peoplewith Down's syndrome: implications for genetic counselling[J].Clin.Genet.,2002,62,390-393.
[19]. Underwood E. Can Down Syndrom Be Treated[J]. Science,2014,343(6174): 964-967.
[20]. Belichenko NP, Belichenko PV, Kleschevnikov AM, et al. The'Down syndrome critical region' is sufficient in the mouse model to confer behavioral, neurophysiological, and synaptic phenotypes characteristic of Down syndrome[J]. J Neurosci,2009,29(18):5938-5948.
[21]. Villar AJ, Belichenko PV, Gillespie AM, et al. Identification and characterization of a new Down syndrome model, Ts[Rb(12.1716)]2Cje, resulting from a spontaneous Robertsonian fusion between T(1716)65Dn and mouse chromosome 12[J]. Mamm Genome,2005,16(2):79-90.
[22]. Olson LE, Tien J, South S, et al. Long-range chromosomal engineering is more efficient in vitro than in vivo[J]. Transgenic Res,2005,14(3):325-332.
[23]. Davisson MT, Schmidt C, Akeson EC. Segmental trisomy of murine chromosome 16:a new model system for studying Down syndrome[J]. Prog Clin Biol Res,1990, 360:263-280.
[24]. Sago H, Carlson EJ, Smith DJ et al. TslCje, a partial trisomy 16 mouse model for Down syndrome, exhibits learning and behavioral abnormalities[J]. Proc Natl Acad Sci USA,1998,95(11):6256-6261.
[25]. Yamakawa, K. Towards the understanding of Down syndrome using mouse models. Congenit Anom(Kyoto).2012,52(2):67-71.
[26]. Kirsammer G, Jilani S, Liu H, et al. Highly penetrant myeloproliferative disease in the Ts65Dn mouse model of Down syndrome[J]. Blood,2008,111(2):767-775.
[27].Nikolaev S I, Santoni F, Vannier A, et al. Exome sequencing identifies putative drivers of progression of transient myeloproliferative disorder to AMKL in infants with Down syndrome[J]. Blood,2013,122(4):554-561.
[28]. Steele A, Scerif G, Cornish K, et al. Learning to read in Williams syndrome and Down syndrome: syndrome - specific precursors and developmental trajectories[J]. Journal of Child Psychology and Psychiatry,2013,54(7):754-762.
[29]. Yoshida K, Toki T, Park M, et al. Genetic basis of myeloid leukemogenesis in Down syndrome[C]//CANCER RESEARCH.615 CHESTNUT ST,17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA:AMER ASSOC CANCER RESEARCH, 2013,73(8).
[30]. Visootsak J, Hess B, Bakeman R, et al. Effect of congenital heart defects on language development in toddlers with Down syndrome[J]. Journal of Intellectual Disability Research,2013,57(9):887-892.
[31]. Zampieri B L, Fernandez F, Pearson J N, et al. Ultrasonic vocalizations during male-female interaction in the mouse model of Down syndrome Ts65Dn[J]. Physiology & behavior,2014,128:119-125.
[32]. Reeves RH, Baxter LL, Richtsmeier JT. Too much of a good thing:mechanisms of gene action in Down syndrome[J]. Trends Genet,2001,17(2):83-88.
[33]. Korenberg JR, Kawashima H, Pulst SM, et al. Molecular definition of a region of chromosome 21 that causes features of the Down syndrome phenotype[J]. Am J Hum Genet,1990,47 (2):236-246.
[34]. Olson LE, Richtsmeier JT, Leszl J, et al. A chromosome 21 critical region does not cause specific Down syndrome phenotypes[J]. Science,2004,06(5696):687-690.
[35]. Wang X, Zhao Y J, Zhang X F, et al. Loss of sorting nexin 27 contributes to excitatory synaptic dysfunction by modulating glutamate receptor recycling in Down's syndrome[J]. Nature Medicine,2013,19(4):473-480.
[36]. American Society of Human Genetics. "Gene-silencing strategy opens new path to understanding Down Syndrome." ScienceDaily. ScienceDaily,22 October 2013. www. sciencedaily.com/releases/2013/10/131022170726.htm.
[37]. Slonim DK, Koide K, Johnson KL, et al. Functional genomic analysis of amniotic fluid cell-free mRNA suggests that oxidative stress is significant in Down syndrome fetuses[J]. Proc Natl Acad Sci USA,2009,106(23):9425-9429.
[38]. Jovanovic SV, Clements D, MacLeod K. Biomarkers of oxidative stress are significantly elevated in Down syndrome[J]. Free Radic Biol Med,1998,25(9): 1044-1048.
[39]. Micali N, Longobardi E, Iotti G, et al. Down syndrome fibroblasts and mouse Prep1-overexpressing cells display increased sensitivity to genotoxic stress[J]. Nucleic Acids Res,2010,38(11):3595-3604.
[40]. Gimeno A, Garcia-Gim6nez J L, Audi L, et al. Decreased cell proliferation and higher oxidative stress in fibroblasts from Down Syndrome fetuses. Preliminary study[J]. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease,2014, 1842(1):116-125.
[41]. Bender CF, Sikes ML, Sullivan R, et al. Cancer predisposition and hematopoietic failure in Rad50(S/S) mice[J]. Genes Dev,2002,16(17):2237-2251.
[42].Nijnik A, Woodbine L, Marchetti C, et al. DNA repair is limiting for haematopoietic stem cells during ageing[J]. Nature,2007,447(7145):686-690.
[43]. Prasher JM, Lalai AS, Heijmans-Antonissen C, et al. Reduced hematopoietic reserves in DNA interstrand crosslinkrepair-deficient Erccl-/- mice[J]. EMBO J, 2005,24(4):861-871.
[44]. Rossi DJ, Bryder D, Seita J, et al. Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age[J]. Nature,2007,447(7145): 725-729.
[45]. Natarajan AT. Radiosensitivity of Cells Derived From Down Syndrome Patients: Is Defective DNA Repair Involved?[A]. In: Baljee AS. DNA Repair and Human Disease[M]. Springer US.
[46]. Chudina AP, Malyutina TS, Progosyane HE. Comparative radiosensitivity of chromosomes in the cultured peripheral blood lymphocytes of normal donors and patients with Down's syndrome[J]. Genetika,1966,4:51-63.
[47].Dekaban ASR, Thron R, Streusing JK. Chromosomal aberrations in irradiated blood and blood cultures of normal subjects and selected patients with chromosomal abnormality[J]. Radiat Res,1966,27(1):50-63.
[48]. Cherry LM, Shukla P, Atwell L. Age, gender, and sensitivity to bleomycin-induced chomosome breakage in Down's syndrome and control populations[J]. Cytobios, 1994,78(312):23-31.
[49]. Ravindran Ankathil, P Kusumakumary, M. Krishnan Nair. Increased Levels of Mutagen-Induced Chromosome Breakage in Down Syndrome Children with Malignancy[J]. Cancer Genet Cytogenet,1997,99(2):126-128.
[50]. Aldenhoff P, Wegner RD, Sperling K. Different sensitivity of diploid and trisomic cells from patients with Down syndrome mosaic after treatment with the trifunctional alkylating agent trenimon[J]. Hum Genet,1980,56(1):123-125.
[51]. Makoto Higurash, Aiko Tada, Shinobu Miyahara, et al. Chromosome Damage in Down's Syndrome Induced by Chickenpox Infection[J]. Pediatric Research,1976, 10(3):189-192.
[52]. Athanasiou K, Sideris EG, Bartsocas C. Decreased repair of X-ray induced DNA single strand breaks in lymphocytes in Down's syndrome[J]. Padiatr Res,1980, 14(4 Pt 1):336-338.
[53]. Lenard JC, Mertz T. Repair of single strand breaks in normal and trisomic lymphocytes[J]. Mutation Res,1982,105(6):417-422.
[54]. Steiner ME, Woods WG. Normal formation and repair of γ-radiation-induced single and double strand DNA breaks in Down syndrome fibroblasts[J]. Mutation Res,1982,95(2-3):515-523.
[55]. Raji NS, Rao KS. Trisomy 21 and accelerated aging: DNA-repair parameters in peripheral lymphocytes of Down's syndrome patients[J]. Mech Ageing Dev,1988, 100(1):85-101.
[56]. Druzhyna N, Nair RG, Ledoux SP, et al. Defective repair of oxidative damage in mitochondrial DNA in Down's syndrome[J]. Mutat Res,1998,409(2):81-89.
[57].Zana M, Sz6cs6nyi A, Czibula A, et al. Age-dependent oxidative stress-induced DNA damage in Down's lymphocytes[J]. Biochem Biophys Res Commun,2006, 345(2):726-733.
[58]. Joo HY, Zhai L, Yang C, et al. Regulation of cell cycle progression and gene expression by H2A deubiquitylation[J]. Nature,2007,449(7165):1068-1072.
[59]. Adorno M, Sikandar S, Mitra SS, et al. Usp16 contributes to somatic stem-cell defects in Down's syndrome[J]. Nature,2013,501(7467):380-384.
[60]. Cuadrado E, Barrena MJ. Immune dysfunction in Down's syndrome: primary immune deficiency or early senescence of the immune system? [J]. Clin Immunol Immunopathol,1996,78(3),209-214.
[61].Mundschau G, Gurbuxani S, Gamis AS, et al. Mutagenesis of GATA1 is an initiating event in Down syndrome leukemogenesis[J]. Blood,2003,101(11): 4298-4300.
[62]. Wechsler J, Greene M, McDevitt MA, et al. Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome[J]. Nat Genet,2002,32(1): 148-152.
[63]. Hitzler JK, Cheung J, Li Y, et al. GATA1 mutations in transient leukemia and acute megakaryoblastic leukemia of Down syndrome[J]. Blood,2003,101(11):4301-4304.
[64]. Alford KA, Reinhardt K, Garnett C, et al. Analysis of GATA1 mutations in Down syndrome TMD and myeloid leukemia[J]. Blood,2011,118(8):2222-2238.
[65]. Russell LJ, Capasso M, Vater L et al. Deregulated expression of cytokine receptor gene, CRLF2, is involved in lymphoid transformation in B-cell precursor acute lymphoblastic leukemia[J]. Blood,2009,114(13):2688-2698.
[66]. Spangrude GJ, Heimfeld S, Weissman IL. Purification and characterization of mouse hematopoietic stem cells[J]. Science,1988,241(4861):58-62.
[67]. Ogawa M, Matsuzaki Y, Nishikawa S, et al. Expression and function of c-kit in hemopoietic progenitor cells[J]. J Exp Med,1991,174(1):63-71.
[68]. Osawa M, Hanada K, Hamada H, Nakauchi H. Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell[J]. Science, 1996,273(5272):242-245.
[69]. Christensen JL, Weissman IL. Flk-2 is a marker in hematopoietic stem cell differentiation: a simple method to isolate long-term stem cells[J]. Proc Natl Acad Sci USA.
[70]. Kiel MJ, Yilmaz OH, Iwashita T, et al. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells[J]. Cell,2005,121(7):1109-1121.
[71]. Ito K, Hirao A, Arai F, et al. Re-active oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells[J]. Nat Med,2006,12(4):446-451.
[72]. Tothova Z, Kollipara R, Huntly BJ, et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress[J]. Cell,2007, 128(2):325-339.
[73], Shao L, Li H, Pazhanisamy SK, et al. Reactive oxygen species and hematopoietic stem cell senescence[J]. Int J Hematol,2011,94(1):24-32.
[74]. Lorenzo LP, Chen H, Shatynski KE, et al. Defective hematopoietic stem cell and lymphoid progenitor development in the Ts65Dn mouse model of Down syndrome: potential role of oxidative stress[J]. Antioxid Redox Signal,2011,15(8):2083-2094.
[75]. Cheshier SH, Morrison SJ, Liao X, et al. In vivo proliferation and cell cycle kinetics of long-term self-renewing hematopoietic stem cells[J]. Proc Natl Acad Sci USA, 1999,96(6):3120-3125.
[76]. Behar TN, Colton CA. Redox regulation of neuronal migration in a Down Syndrome model[J]. Free Radic Biol Med,2003,35(6):566-575.
[77]. Yamamoto H, Tang H. Melatonin attenuates L-cysteine-induced seizures and lipid peroxidation in the brain of mice[J]. J Pineal Res,1996,21(2):108-113.
[78]. Yamamoto H. Preventive effect of N(G)-nitro-L-arginine against L-cysteine-induced seizures in mice[J]. Toxicol Lett,1996,84(1):1-5.
[79], Hershkovitz E, Shorer Z, Levitas A, et al. Status epilepticus following intravenous N-acetylcysteine therapy [J]. Isr J Med Sci,1996,32(11):1102-1104.
[80].Blake CCF, Phillips DC. Effects of X-irradiation on single crystals of myoglobin[A]. in proceedings of a symposium held at Brno. Biological Effects of Ionizing Radiation at the Molecular Level, proceedings of a symposium held at Brno[[C]. Vienna:International Atomic Energy Agency.1962:183-191.
[81]. Haber JE. Partners and pathways repairing a double-strand break[J]. Trends Genet, 2000,16 (6):259-264.
[82]. Lieber MR. The mechanism of human nonhomologous DNA end joining[J]. J Biol Chem,2008,283 (1):1-5.
[83]. Sonoda E, Hochegger H, Saberi A, et al. Differential usage of non-homologous end-joining and homologous recombination in double strand break repair[J]. DNA Repair (Amst),2006,5 (9-10):1021-1029.
[84]. Shrivastav M, De Haro LP, Nickoloff JA. Regulation of DNA double-strand break repair pathway choice[J]. Cell Res,2008,18 (1):134-147.
[85]. Mohrin M, Bourke E, Alexander D, et al. Hematopoietic stem cell quiescence promotes error prone DNA repair and mutagenesis[J]. Cell Stem Cell,2010,7(2): 174-185.
[86]. West MH, Bonner WM. Histone 2A, a heteromorphous family of eight protein species[J]. Biochemistry,1980,19 (14):3238-3245.
[87]. Rogakou EP, Pilch DR, Orr AH, et al. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139[J]. J Biol Chem,1998,273 (10):5858-5868.
[88]. Rothkamm K, Horn S. Gamma-H2AX as protein biomarker for radiation exposure[J]. Ann 1st Super Sanita,2009,45 (3):265-271.
[89]. Redon CE, Dickey JS, Bonner WM, et al. Gamma-H2AX as a biomarker of DNA damage induced by ionizing radiation in human peripheral blood lymphocytes and artificial skin[J]. Adv Space Res,2009,43 (8):1171-1178.
[90]. Shanbhag NM, Rafalska-Metcalf IU, Balane-Bolivar C, et al. ATM-dependent chromatin changes silence transcription in cis to DNA double-strand breaks[J]. Cell, 2010,141(6):970-981.
[91].Mattiroli F, Vissers JH, van Dijk WJ, et al. RNF168 ubiquitinates K13-15 on H2A/H2AX to drive DNA damage signaling[J]. Cell,2012,150(6):1182-1195.
[92]. Uhrhammer NA, Lafarge L, Dos Santos L, et al. Werner syndrome and mutations of the WRN and LMNA genes in France[J]. Hum Mutat,2006,27(7):718-719.
[93]. Moser MJ, Oshima J, Monnat RJ Jr. WRN mutations in Werner syndrome[J]. Hum Mutat,1999,13(4):271-270.
[94]. Kusumoto-Matsuo R, Ghosh D, Karmakar P, et al. Serines 440 and 467 in the Werner syndrome protein are phosphorylated by DNA-PK and affects its dynamics in response to DNA double strand breaks[J]. Aging(Albany NY),2014,6(l):70-81.
[95]. li B, lglesias-Pedraz JM, Chen LY, et al. Downregulation of the Werner syndrome protein induces a metabolic shift that compromises redox homeostasis and limits proliferation of cancer cells. Aging cell,2014,13(2):367-378.
[96].Arora H, Chacon AH, Choudhary S, et al. Bloom syndrome[J]. Int J Dermatol,2014, doi.10.1111/ijd.12408. [Epub ahead of print].
[97]. Salah GB, Salem IH, masmoudi A, et al. Chromosomal instability associated with a novel BLM frameshift mutation (c.1980-1982delAA) in two unrelated Tunisian families with Bloom syndrome[J]. J Eur Acad Dermatol Venereol,2013, doi: 10.1111/jdv.12279. [Epub ahead of print].
[98]. Grabarz A, Guiouilh-Barbat J, Barascu A. et al. A role for BLM in double-strand break repair pathway choice: prevention of CtlP/Mrel1-mediated alternative nonhomologous end-joining[J]. Cell Rep,2013,5(1):21-28.
[99]. Hisata S, Sakaguchi H, Kanegane H, et al. A Novel Missense Mutation of DKC1 in Dyskeratosis Congenita With Pulmonary Fibrosis[J]. Sarcoidosis Vasc Diffuse Lung Dis,2013,30(3):221-225.
[100]. Kirwan M, Beswick R, Vulliamy T, et al. Exogenous TERC alone can enhance proliferative potential, telomerase activity and telomere length in lymphocytes from dyskeratosis congenita patients[J]. Br J Haematol,2009,144(5):771-781.
[101]. Gourronc FA, Robertson mM, herrig AK, et al. Proliferative defects in dyskeratosis congenita skin keratinocytes are corrected by expression of the telomerase reverse transcriptase, TERT, or by activation of endogenous telomerase through expression of papillomavirus E6/E7 or the telomerase RNA component, TERC[J]. Exp Dermatol,2010,19(3):279-288.
[102]. O'Connell N, Goodyer M, Gleeson M, et al. Successful treatment with rituximab and mycophenolate mofetil of refractory autoimmune hemolytic anemia post-hematopoietic stem cell transplant for dyskeratosis congenita due to TINF2 mutation[J]. Pediatr Transplant,2014,18(1):E22-24.
[103]. Pereboeva L, Westin E, Patel T, et al. DNA damage responses and oxidative stress in dyskeratosis congenita[J]. PLoS One,2013,8(10):e76473.
[104]. Sheltzer JM, Blank HM, Pfau SJ, et al. Aneuploidy drives genomic instability in yeast[J]. Science,2011,333(6045):1026-1030.
[105]. Aaltonen LA, Peltomaki P, Leach FS, et al. Clues to the pathogenesis of familial colorectal cancer[J]. Science,1993,260(5109):812-816.
[106]. Watatani M, Yoshida T, Kuroda K, et al. Allelic loss of chromosome 17p, mutation of the p53 gene, and microsatellite instability in right- and left-sided colorectal cancer[J]. Cancer,1996,77(8):1688-1693.
[107]. Hershko A, Ciechanover A. The ubiquitin system[J]. Annual Review of Biochemistry,1998,67:425-479.
[108]. Clague MJ, Urb6 S. Ubiquitin: same molecule, different degradation pathways[J]. Cell,2010,143(5):682-685.
[109]. Neutzner M, Neutzner A. Enzymes of ubiquitination and deubiquitination[J]. EssaysBiochem,2012,52(1):37-50.
[110]. Varshavsky A. The ubiquitin system, an immense realm[J]. Annu Rev Biochem, 2012,81:167-176.
[111]. Komander D, Rape M. The ubiquitin code[J]. Annu Rev Biochem,2012,81: 203-229.
[112]. Adorno M, Sikandar S, Mitra SS, et al, Usp16 contributes to somatic stem-cell defects in Down's syndrome. Nature,2013:p.501(7467):7380-7384.
[113]. Ciccia A, Elledge SJ. The DNA damage response: Making it safe to play with knives[J]. Molecular Cell,2010,40(2):179-204.
[114]. Jackson SP, Bartek J. The DNA-damage response in human biology and disease[J]. Nature,2009,461(7267):1071-1078.
[115]. Branzei D, Foiani M. Regulation of DNA repair throughout the cell cycle[J]. Nat Rev Mol Cell Biol,2008,9(4):297-308.
[1]. Souroullas G P, Sharpless N E. Stem cells: Down's syndrome link to ageing[J]. Nature,2013,501(7467):325-326.
[2]. Ward OC. John Langdon Down:the man and the message[J]. Downs syndr Res Pract,1999,6(1):19-24.
[3]. Megarbane A, Ravel A, Mrcher C, et al. The 50th anniversary of the discovery of trisomy 21:the past, present, and future of research and treatment of Down syndrome[J]. Genet Med,2009,11(9):611-616.
[4]. Gardiner, KJ. Molecular basis of pharmacotherapies for cognition in Down syndrome[J]. Trends Pharmacol Sci,2010,31(2):66-73.
[5]. de Graaf G, Haveman M, Hochstenbach R, et al. Changes in yearly birth prevalence rates of children with Down syndrome in the period 1986-2007 in The Netherlands[J]. J Intellect Disabil Res,2011,55(5):462-473.
[6]. Antonarakis SE, Lyle R, Dermitzakis ET, et al. Chromosome 21 and Down syndrome: from genomics to pathophysiology[J]. Nature Rev Genet,2004,5(10): 725-738.
[7]. Yang Q, Rasmussen SA, Friedman J M. Mortality associated with Down's syndrome in the USA from 1983 to 1997:a population-based study[J]. Lancet,2002, 359(9311):1019-1025.
[8]. Roth GM, Sun B, Greensite FS, et al. Premature aging in persons with Down syndrome: MR findings[J]. Am. J. Neuroradiol,1996,17(7):1283-1289.
[9]. Zigman WB, Lott IT. Alzheimer's disease in Down syndrome: neurobiology and risk[J]. Ment Retard Dev Disabil Res Rev,2007,13(3):237-246.
[10]. Izraeli S, Rainis L, Hertzberg L, et al. Trisomy of chromosome 21 in leukemogenesis[J]. Blood Cells Mol Dis,2007,39(2):156-159.
[11]. Kusters MA, Verstegen RH, Gemen EF, et al. In-trinsic defect of the immune system in children with Down syndrome: a review[J]. Clin Exp Immunol,2009, 156(2):189-193.
[12]. Hasle H, Clemmensen IH, Mikkelsen M. Risks of leukaemia and solid tumours in individuals with Down's syndrome[J]. Lancet,2000,355(9199):165-169.
[13]. Whitlock JA, Sather HN, Gaynon P, et al. Clinical characteristics and outcome of children w ith Down syndrome and acute lymphoblastic leukemia: A Children's Cancer Group study[J]. Blood,2005,106(13):4043-4049.
[14]. Stefanidis K, Belitsos P, Fotinos A, et al. Causes of infertility in men with Down syndrome[J]. Andrologia,2011,43(5):353-357.
[15].Manila Kaushal, Asha Baxi, Pooja Kadi, et al. Woman with Down Syndrome delivered a Normal Child[J]. International Journal of Infertility and Fetal Medicine, 2010,1(1):45-47.
[16]. Glasson, E.J., Sullivan, S.G., Hussain, R., Petterson, B.A., Montgomery,P.D. and Bittles, A.H. The changing survival profile of peoplewith Down's syndrome: implications for genetic counselling[J].Clin.Genet.,2002,62,390-393.
[17]. Cuadrado E, Barrena MJ. Immune dysfunction in Down's syndrome: primary immune deficiency or early senescence of the immune system? [J]. Clin Immunol Immunopathol,1996,78(3),209-214.
[18].Mundschau G, Gurbuxani S, Gamis AS, et al. Mutagenesis of GATA1 is an initiating event in Down syndrome leukemogenesis[J]. Blood,2003,101(11): 4298-4300.
[19]. Spangrude GJ, Heimfeld S, Weissman IL. Purification and characterization of mouse hematopoietic stem cells[J]. Science,1988,241(4861):58-62.
[20]. Ogawa M, Matsuzaki Y, Nishikawa S, et al. Expression and function of c-kit in hemopoietic progenitor cells[J]. J Exp Med,1991,174(1):63-71.
[21]. Osawa M, Hanada K, Hamada H, Nakauchi H. Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell[J]. Science, 1996,273(5272):242-245.
[22]. Christensen JL, Weissman IL. Flk-2 is a marker in hematopoietic stem cell differentiation: a simple method to isolate long-term stem cells[J]. Proc Natl Acad Sci USA.
[23].Kiel MJ, Yilmaz OH, Iwashita T, et al. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells[J]. Cell,2005,121(7):1109-1121.
[24]. Belichenko NP, Belichenko PV, Kleschevnikov AM, et al. The 'Down syndrome critical region1 is sufficient in the mouse model to confer behavioral, neurophysiological, and synaptic phenotypes characteristic of Down syndrome[J]. J Neurosci,2009,29(18):5938-5948.
[25].Davisson MT, Schmidt C, Akeson EC. Segmental trisomy of murine chromosome 16:a new model system for studying Down syndrome[J]. Prog Clin Biol Res,1990, 360:263-280.
[26]. Sago H, Carlson EJ, Smith DJ et al. Ts1Cje, a partial trisomy 16 mouse model for Down syndrome, exhibits learning and behavioral abnormalities[J]. Proc Natl Acad Sci USA,1998,95(11); 6256-6261.
[27]. Villar AJ, Belichenko PV, Gillespie AM, et al. Identification and characterization of a new Down syndrome model, Ts[Rb(12.1716)]2Cje, resulting from a spontaneous Robertsonian fusion between T(1716)65Dn and mouse chromosome 12[J]. Mamm Genome,2005,16(2):79-90.
[28]. Olson LE, Tien J, South S, et al. Long-range chromosomal engineering is more efficient in vitro than in vivo[J]. Transgenic Res,2005,14(3):325-332.
[29]. Yamakawa, K. Towards the understanding of Down syndrome using mouse models. Congenit Anom(Kyoto).2012,52(2):67-71.
[30]. Zampieri B L, Fernandez F, Pearson J N, et al. Ultrasonic vocalizations during male-female interaction in the mouse model of Down syndrome Ts65Dn[J]. Physiology & behavior,2014,128:119-125.
[31]. Visootsak J, Hess B, Bakeman R, et al. Effect of congenital heart defects on language development in toddlers with Down syndrome[J]. Journal of Intellectual Disability Research,2013,57(9):887-892.
[32]. Kirsammer G, Jilani S, Liu H, et al. Highly penetrant myeloproliferative disease in the Ts65Dn mouse model of Down syndrome[J]. Blood,2008,111(2):767-775.
[33]. Wechsler J, Greene M, McDevitt MA, et al. Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome[J]. Nat Genet,2002,32(1): 148-152.
[34]. Hitzler JK, Cheung J, Li Y, et al. GATA1 mutations in transient leukemia and acute megakaryoblastic leukemia of Down syndrome[J]. Blood,2003,101(11):4301-4304.
[35]. Alford KA, Reinhardt K, Garnett C, et al. Analysis of GATA1 mutations in Down syndrome TMD and myeloid leukemia[J]. Blood,2011,118(8):2222-2238.
[36]. Russell LJ, Capasso M, Vater I, et al. Deregulated expression of cytokine receptor gene, CRLF2, is involved in lymphoid transformation in B-cell precursor acute lymphoblastic leukemia[J]. Blood,2009,114(13):2688-2698.
[37]. Lorenzo LP, Chen H, Shatynski KE, et al. Defective hematopoietic stem cell and lymphoid progenitor development in the Ts65Dn mouse model of Down syndrome: potential role of oxidative stress[J]. Antioxid Redox Signal,2011,15(8):2083-2094.
[38]. Reeves RH, Baxter LL, Richtsmeier JT. Too much of a good thing:mechanisms of gene action in Down syndrome[J]. Trends Genet,2001,17(2):83-88.
[39]. Korenberg JR, Kawashima H, Pulst SM, et al. Molecular definition of a region of chromosome 21 that causes features of the Down syndrome phenotype[J]. Am J Hum Genet,1990,47 (2):236-246.
[40]. Olson LE, Richtsmeier JT, Leszl J, et al. A chromosome 21 critical region does not cause specific Down syndrome phenotypes[J]. Science,2004,06(5696):687-690.
[41]. Slonim DK, Koide K, Johnson KL, et al. Functional genomic analysis of amniotic fluid cell-free mRNA suggests that oxidative stress is significant in Down syndrome fetuses[J]. Proc Natl Acad Sci USA,2009,106(23):9425-9429.
[42]. Ito K, Hirao A, Arai F, et al. Re-active oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells[J]. Nat Med,2006,12(4):446-451.
[43]. Tothova Z, Kollipara R, Huntly BJ, et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress[J]. Cell,2007, 128(2):325-339.
[44]. Shao L, Li H, Pazhanisamy SK, et al. Reactive oxygen species and hematopoietic stem cell senescence[J]. Int J Hematol,2011,94(1):24-32.
[45].Behar TN, Colton CA. Redox regulation of neuronal migration in a Down Syndrome model[J]. Free Radic Biol Med,2003,35(6).566-575.
[46], Yamamoto H, Tang H. Melatonin attenuates L-cysteine-induced seizures and lipid peroxidation in the brain of mice[J]. J Pineal Res,1996,21(2):108-113.
[47]. Yamamoto H. Preventive effect of N(G)-nitro-L-arginine against L-cysteine-induced seizures in mice[J]. Toxicol Lett,1996,84(1):1-5.
[48]. Hershkovitz E, Shorer Z, Levitas A, et al. Status epilepticus following intravenous N-acetylcysteine therapy[J]. Isr J Med Sci,1996,32(11):1102-1104.
[49].Blake CCF, Phillips DC. Effects of X-irradiation on single crystals of myoglobin[A]. in proceedings of a symposium held at Brno. Biological Effects of Ionizing Radiation at the Molecular Level, proceedings of a symposium held at Brno[[C]. Vienna: International Atomic Energy Agency.1962:183-191.
[50]. Haber JE. Partners and pathways repairing a double-strand break[J]. Trends Genet, 2000,16 (6):259-264.
[51]. Lieber MR. The mechanism of human nonhomologous DNA end joining[J]. J Biol Chem,2008,283(1):1-5.
[52]. Sonoda E, Hochegger H, Saberi A, et al. Differential usage of non-homologous end-joining and homologous recombination in double strand break repair[J]. DNA Repair (Amst.),2006,5 (9-10):1021-1029.
[53]. Shrivastav M, De Haro LP, Nickoloff JA. Regulation of DNA double-strand break repair pathway choice[J]. Cell Res,2008,18 (1):134-147.
[54]. Mohrin M, Bourke E, Alexander D, et al. Hematopoietic stem cell quiescence promotes error prone DNA repair and mutagenesis[J]. Cell Stem Cell,2010,7(2): 174-185.
[55]. Bender CF, Sikes ML, Sullivan R, et al. Cancer predisposition and hematopoietic failure in Rad50(S/S) mice[J]. Genes Dev,2002,16(17):2237-2251.
[56]. Nijnik A, Woodbine L, Marchetti C, et al. DNA repair is limiting for haematopoietic stem cells during ageing[J]. Nature,2007,447(7145):686-690.
[57]. Prasher JM, Lalai AS, Heijmans-Antonissen C, et al. Reduced hematopoietic reserves in DNA interstrand crosslinkrepair-deficient Erccl-/- mice[J]. EMBO J, 2005,24(4):861-871.
[58]. Rossi DJ, Bryder D, Seita J, et al. Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age[J]. Nature,2007,447(7145): 725-729.
[59].Natarajan AT. Radiosensitivity of Cells Derived From Down Syndrome Patients:Is Defective DNA Repair Involved?[A]. In: Baljee AS. DNA Repair and Human Disease[M]. Springer US.
[60]. Chudina AP, Malyutina TS, Progosyane HE. Comparative radiosensitivity of chromosomes in the cultured peripheral blood lymphocytes of normal donors and patients with Down's syndrome[J]. Genetika,1966,4:51-63.
[61]. Dekaban ASR, Thron R, Streusing JK. Chromosomal aberrations in irradiated blood and blood cultures of normal subjects and selected patients with chromosomal abnormality [J]. Radiat Res,1966,27(1):50-63.
[62]. Cherry LM, Shukla P, Atwell L. Age, gender, and sensitivity to bleomycin-induced chomosome breakage in Down's syndrome and control populations[J]. Cytobios, 1994,78(312):23-31.
[63]. Ravindran Ankathil, P Kusumakumary, M. Krishnan Nair. Increased Levels of Mutagen-Induced Chromosome Breakage in Down Syndrome Children with Malignancy[J]. Cancer Genet Cytogenet,1997,99(2):126-128.
[64]. Aldenhoff P, Wegner RD, Sperling K. Different sensitivity of diploid and trisomic cells from patients with Down syndrome mosaic after treatment with the trifunctional alkylating agent trenimon[J]. Hum Genet,1980,56(1):123-125.
[65]. Makoto Higurash, Aiko Tada, Shinobu Miyahara, et al. Chromosome Damage in Down's Syndrome Induced by Chickenpox Infection[J]. Pediatric Research,1976, 10(3):189-192.
[66]. Athanasiou K, Sideris EG, Bartsocas C. Decreased repair of X-ray induced DNA single strand breaks in lymphocytes in Down's syndrome[J]. Padiatr Res,1980, 14(4 Pt 1):336-338.
[67]. Lenard JC, Mertz T. Repair of single strand breaks in normal and trisomic lymphocytes[J]. Mutation Res,1982,105(6):417-422.
[68]. Steiner ME, Woods WG. Normal formation and repair of y-radiation-induced single and double strand DNA breaks in Down syndrome fibroblasts[J]. Mutation Res, 1982,95(2-3):515-523.
[69]. Raji NS, Rao KS. Trisomy 21 and accelerated aging: DNA-repair parameters in peripheral lymphocytes of Down's syndrome patients[J]. Mech Ageing Dev,1988, 100(1):85-101.
[70]. Druzhyna N, Nair RG, Ledoux SP, et al. Defective repair of oxidative damage in mitochondrial DNA in Down's syndrome[J]. Mutat Res,1998,409(2):81-89.
[71].Zana M, Szecsenyi A, Czibula A, et al. Age-dependent oxidative stress-induced DNA damage in Down's lymphocytes[J]. Biochem Biophys Res Commun,2006, 345(2):726-733.
[72]. Hershko A, Ciechanover A. The ubiquitin system[J]. Annual Review of Biochemistry,1998,67:425-479.
[73]. Clague MJ, Urbe S. Ubiquitin: same molecule, different degradation pathways[J]. Cell,2010,143(5):682-685.
[74].Neutzner M, Neutzner A. Enzymes of ubiquitination and deubiquitination[J]. EssaysBiochem,2012,52(1):37-50.
[75]. Varshavsky A. The ubiquitin system, an immense realm[J]. Annu Rev Biochem, 2012,81:167-176.
[76]. Komander D, Rape M. The ubiquitin code[J]. Annu Rev Biochem,2012,81: 203-229.
[77]. West MH, Bonner WM. Histone 2A, a heteromorphous family of eight protein species[J]. Biochemistry,1980,19 (14):3238-3245.
[78]. Rogakou EP, Pilch DR, Orr AH, et al. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139[J]. J Biol Chem,1998,273 (10):5858-5868.
[79]. Shanbhag NM, Rafalska-Metcalf IU, Balane-Bolivar C, et al. ATM-dependent chromatin changes silence transcription in cis to DNA double-strand breaks[J]. Cell, 2010,141(6):970-981.
[80]. Mattiroli F, Vissers JH, van Dijk WJ, et al. RNF168 ubiquitinates K13-15 on H2A/H2AX to drive DNA damage signaling[J]. Cell,2012,150(6):1182-1195.
[81]. Adorno M, Sikandar S, Mitra SS, et al, Usp16 contributes to somatic stem-cell defects in Down's syndrome. Nature,2013:p.501(7467):7380-7384.
[1]Hofer M, Pospisil M, Hoferova Z, et al. Stimulatory action of cyclooxygenase inhibitors on hematopoiesis: a review[J]. Molecules,2012,17(5):5615-5625.
[2]Gentile P, Byer D, Pelus LM. In vivo modulation of murine myelopoiesis following intravenous administration of prostaglandin E2[J]. Blood,1983,62(5):1100-1107.
[3]Pelus LM. Association between colony forming units-granulocyte macrophage expression of la-like (HLA-DR) antigen and control of granulocyte and macrophage production[J]. A new role for prostaglandin E. J Clin Invest,1982, 70(3):568-578.
[4]Pelus LM. Blockade of prostaglandin biosynthesis in intact mice dramatically augments the expansion of committed myeloid progenitor cells (colony-forming units-granulocyte, macrophage) after acute administration of recombinant human IL-1 alpha[J]. J Immunol,1989,143(12):4171-4179.
[5]Pelus LM, Hoggatt J, Singh P. Pulse exposure of haematopoietic grafts to prostaglandin E2 in vitro facilitates engraftment and recovery [J]. Cell Prolif,2011, 44 Suppl1:S22-29.
[6]Pelus LM, Hoggatt J. Pleiotropic effects of prostaglandin E2 in hematopoiesis; prostaglandin E2 and other eicosanoids regulate hematopoietic stem and progenitor cell function[J], Prostaglandins Other Lipid Mediat,2011,96(1-4):3-9.
[7]Hoggatt J, Singh P, Stilger KN, et al. Recovery from hematopoietic injury by modulating prostaglandin E(2) signaling post-irradiation[J]. Blood Cells Mol Dis, 2013,50(3):147-153.
[8]Ludin A, Itkin T, Gur-Cohen S, et al. Monocytes-macrophages that express a-smooth muscle actin preserve primitive hematopoietic cells in the bone marrow[J]. Nat Immunol,2012,13(11):1072-1082.
[9]Lord AM, North TE, Zon LI. Prostaglandin E2:making more of your marrow[J]. Cell Cycle,2007,6(24):3054-3057.
[10]Park JY, Pillinger MH, Abramson SB. Prostaglandin E2 synthesis and secretion: the role of PGE2 synthases[J]. Clin Immunol,2006,119(3):229-240.
[11]Murakami M, Kudo I. Prostaglandin E synthase: a novel drug target for inflammation and cancer[J]. Curr Pharm Des,2006,12(8):943-954.
[12]Rundhaug JE, Simper MS, Surh I, et al. The role of the EP receptors for prostaglandin E2 in skin and skin cancer[J]. Cancer Metastasis Rev,2011,30(3-4): 465-480.
[13]Hoggatt J, Singh P, Sampath J, et al. Prostaglandin E2 enhances hematopoietic stem cell homing, survival, and proliferation[J]. blood,2009,113(22):5444-5455.
[14]Zou YR, Kottmann AH, Kuroda M, et al. Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development J]. Nature,1998, 393(6685):595-599.
[15]Lorenz M, Slaughter HS, Wescott DM, et al. Cyclooxygenase-2 is essential for normal recovery from 5-fluorouracil-induced myelotoxicity in mice[J]. Exp Hematol,1999,27(10):1494-1502.
[16]North TE, Goessling W, Walkley CR, et al. Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis[J]. Nature,2007,447(7147): 1007-1011.
[17]Frisch BJ, Porter RL, Gigliotti BJ, et al. In vivo prostaglandin E2 treatment alters the bone marrow microenvironment and preferentially expands short-term hematopoietic stem cells[J]. Blood,2009,114(19):4054-4063.
[18]Goessling W, North TE, Loewer S, et al. Genetic interaction of PGE2 and Wnt signaling regulates developmental specification of stem cells and regeneration[J]. cell,2009,136(6):1136-1147.
[19]Goessling W, Allen RS, Guan X, et al. Prostaglandin E2 enhances human cord blood stem cell xenotransplants and shows long-term safety in preclinical nonhuman primate transplant models[J]. Cell Stem Cell,2011,8(4):445-458.