THE FUNCTION OF RECQ HELICASE GENE FAMILY IN DNA RECOMBINATION AND JOINING

• Project/Area Number: 10216204
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: GIFU UNIVERSITY
• Principal Investigator: KONDO Naomi GIFU UNIVERSITY, SCHOOL OF MEDICINE, PROFESSOR, 医学部, 教授 (50124714)
• Co-Investigator(Kenkyū-buntansha): KANEKO Hideo GIFU UNIVERSITY, SCHOOL OF MEDICINE, LECTURER, 医学部, 講師 (80293554)
• Project Period (FY): 1998 – 2002
• Project Status: Completed (Fiscal Year 2003)
• Budget Amount: ¥36,000,000 (Direct Cost: ¥36,000,000); Fiscal Year 2002: ¥6,000,000 (Direct Cost: ¥6,000,000); Fiscal Year 2001: ¥5,900,000 (Direct Cost: ¥5,900,000); Fiscal Year 2000: ¥7,700,000 (Direct Cost: ¥7,700,000); Fiscal Year 1999: ¥7,900,000 (Direct Cost: ¥7,900,000); Fiscal Year 1998: ¥8,500,000 (Direct Cost: ¥8,500,000)
• Keywords: Bloom syndrome / BLM / ataxia-telangiectasia / DT40 / double knock out / radiation sensitivity / sister chromatid exchange / ATM / 非相同組み換え / helicase domain / リン酸化 / telomerase / SUMO-1 / 相互作用 / 細胞死 / ノックアウトマウス / 患者スクリーニング / イムノブロット / マイトジェン / リンパ球の分化 / ヘリカーゼ / DNA修復 / DNA切断

Research Abstract

Bloom syndrome and ataxia-telangiectasia are autosomal recessive human disorders characterized by immunodeficiency, genome instability and predisposition to develop cancer. Recent data reveal that the products of these two genes, BLM and ATM, interact and function together in recognizing abnormal DNA structures. To investigate the function of these two molecules in DNA damage, recognition, we generated double knockouts of ATM-/-BLM-/-In the DT40 chicken B-lymphocyte cell line. The double mutant cells were viable and exhibited a variety of characteristics of both ATM-/-and BLM-/-cells. There was no evidence for exacerbation of either phenotypes ; however, the more extreme radiosensitivity seen in ATM-/-and elevated sister chromatid exchange seen in BLM-/-cells were retained in the double mutants. These results suggest that ATM and BLM have largely distinct roles in recognizing different forms of damage in DNA, but also compatible with partially overlapping functions in recognizing breaks in radiation-damaged DNA.
In addition, we showed that the combinational analysis of immunoblotting and immunohistochemistry is a useful approach to screening of BS.

Research Products

• [Publications] Fukao, T., Kondo, N.et al.: "Disruption of the BLM gene in ATM-null DT40 cells dose not exacerbate either phenotype."Oncogene. (in press).
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Terada, T., Kaneko, H.et al.: "Semiquantative evaluation of mRNAs for membraneous form of immunoglobulin heavy chain is useful for investigating the etiology"Scand J Immunol.. 58. 649-654 (2003)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Kato, Z., Kondo, N.et al.: "Structure of interleukin-18 and the binding mode."Nat Struct Biol. 10. 966-971 (2003)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Kasahara, Y., Kaneko, H.et al.: "Hyper-IgM syndrome with putataive dominant negative mutation in activation-induced cytidine deaminase"J.Allergy Clin.Immunol.. 112. 755-760 (2003)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Morimoto, W., Kaneko, H.et al.: "Expression of BLM (the causative gene for Bloom syndrome) and screening of Bloom syndrome."Int J Mol Med. 10. 95-99 (2002)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Beamish, H., Kondo, N.et al.: "Functional link between BLM defective in Bloom's syndrome and the ataxia-telangiectasia mutated protein, ATM."J Blol Chem. 277. 30515-30523 (2002)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Matui, E., Kaneko, H.et al.: "Current advances in pediatric asthma and other allergic diseases. Edited by Morikawa A"JOMO NEWSPAPER Co., Ltd.. 37-42 (2002)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Fukao, T., Kondo, N.: "Disruption of the BLM gene in ATM-null DT40 cells dose not exacerbate either phenotype."Oncogene in press.
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Terada, T., Kaneko, H.: "Semiquantative evaluation of mRNAs for membraneous form of immunoglobulin heavy chain is useful for investigating the etiology in CVID"Scand Immunol.. 58. 649-654 (2003)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Kato, Z., Kondo, N.: "Structure of interleukin-18 and the binding mode."Nat Struct Biol. 10. 966-971 (2003)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Kasahara, Y., Kaneko, H.: "Hyper-IgM syndrome with putataive dominant negative mutation in activation-induced cytidine deaminase."J Allergy Clin Immunol. 11. 755-760 (2003)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Morimoto, W., Kaneko, H.: "Expression of BLM (the causative gene for Bloom syndrome) and screening of Bloom syndrome."Int J Mol Med. 10. 95-99 (2002)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Beamish, H., Kondo, N.: "Functional link between BLM defective in Bloom's syndrome and the ataxia-telangiectasia mutated protein, ATM."J Biol Chem. 277. 30515-30523 (2002)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Matui, E., Kaneko, H.: "Current advances in pediatric asthma and other allergic diseases. Edited by Morikawa A"JOMO NEWSPAPER Co., Ltd.. 37-42 (2002)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Kondo, N., Matsui, E., et al.: "Review : Atopy and mutations of II-12 receptor β2 chain gene"Clin Exp Allergy. 31. 1189-1193 (2001)
• [Publications] Terada, T., Kondo, N., et al.: "Analysis of Ig subclass deficiency : First reported case of IgG2, IgG4, and IgA deficiency caused by deletion of Cα1, ψCγ2, Cγ4 and C ε in a Mongoloid patient"J Allergy Clin Immunol. 108. 602-606 (2001)
• [Publications] Watanabe, M., Kondo, N., et al.: "Predominant expression of 950delCAG of IL-18R alpha chain cDNA is nd associated with reduced IFN-gamma production and high serum IgE levels in atonic Japanese children"J Allergy Clin Immunol. 109. 669-675 (2002)
• [Publications] Morimoto, W., Kondo, N., et al.: "Expression of BLM (the causative gene for Bloom syndrome) and screening of Bloom syndrome"Int J Mol Med. 10. 95-99 (2002)
• [Publications] Sakaguchi, H., Konodo, N., et al.: "Interaction among human leucocyte antigen-peptide-T cell receptor complexes in cow's milk allergy : the significance of human leucocyte antigen and T cell receptor-complementarity determining region 3 loops"Clin Exp Allergy. 32. 762-770 (2002)
• [Publications] Beamish H, Kaneko H, Kondo N., et al.: "Functional link between BLM defective in Bloom's syndrome and the ataxia-telangiectasia-mutated protein, ATM"J Biol Chem.. 277. 30515-30523 (2002)
• [Publications] 近藤直実: "IgEクラススイッチ"メデイカルレビュー社. 271 (2001)
• [Publications] Kondo, N., Matsui, E., et al.: "Reduced interferon-gamma production and mutations of the interleukin-12 receptor beta(2) chain gene in atopic subjects"Int Arch Allergy Immunol. 124. 117-120 (2001)
• [Publications] Kondo, N., Matsui, E., et al.: "Review : Atopy and mutations of 11-12 receptor β2 chain gene"Clin Exp Allergy. 31. 1189-1193 (2001)
• [Publications] Kondo, N.: "Clinical and genetic research of food allergy in childhood"Journal of Asthma Allergy and Clinical Immunology. 21. 1063-1065 (2001)
• [Publications] Terada, T., Kondo, N.et al.: "Analysis of Ig subclass deficiency : First reported case of IgG2, IgG4, and IgA deficiency caused by deletion of Cα1, ψCγ, Cγ2, Cγ4, and Cε in a Mongoloid patient"J Allergy Clin Immunol. 108. 602-606 (2001)
• [Publications] Watanabe, M., Kondo, N.et al.: "Predominant expression of 95OdelCAG of IL-18R alpha chain cDNA is associated with reduced IFN-gamma production and high serum IgE level in atopic Japanese children"J Allergy Clin Immunol. (in press).
• [Publications] Kaneko, H., Kondo, N.et al.: "Telomerase activity in cell lines and lymphoma originating from Bloom syndrome"Leukemia and Lymphoma. 42. 757-760 (2001)
• [Publications] 近藤直実: "先天性免疫不全症を耳鼻咽喉疾患"中山書店. 40-353 (2001)
• [Publications] Kondo N, et al.: "Atopy and mutation of IL-12 receptor β2 chain gene."Clin Exp Allergy. (in press). (2001)
• [Publications] Hayakawa S,Kaneko H,Kondo N, et al.: "Characterization of the nuclear localization signal in the DNA helicase responsible for Bloom syndrome."Int.J.Mol.Med.. 5. 477-484 (2000)
• [Publications] Fukao T,Kondo N, et al.: "Immunoblot analysis for laboratory diagnosis of ataxia-telangiectasia : Use of Epstein-Barr virus-transformed or phytohemagglutinin-stimulated lymphoblasts for detection of ATM protein."J Invest Allergol Clin Immunol. 10. 36-40 (2000)
• [Publications] Motano AM,Kondo N, et al.: "The mouse N-acetylgalactosamine-6-sulfate sulfatase (Galns) gene : cDNA isolation, genomic characterization, chromosomal assignment and analysis of the 5'-flanking region."Biochem Biophys Acta. 1500. 323-334 (2000)
• [Publications] Sukegawa K,Kondo N, et al.: "Biochemical and structural analysis of missense mutation in N-acetylgalactosamine-6-sulfate sulfatase causing mucopolysaccharidosis IVA phenotypes."Hum Mol Genet. 9. 1283-1290 (2000)
• [Publications] Terada T,Kondo N, et al.: "Fate of the mutation IgG2 heavy chain : lack of expression of mutated membrane-bound IgG2 on the B cell surface in selective IgG2 deficiency."Int Immunol. 13. 249-256 (2001)
• [Publications] 近藤直実: "先天性(原発性)免疫不全症:コンパクト臨床アレルギー学"南江堂. 328-343 (2000)
• [Publications] Kondo N, et al.: "Role of IL-12 receptor β2 mutations in development of atopy."Allergy & Clinical Immunology International. 92-94 (2000)
• [Publications] Kaneko H, Kondo N, et al.: "Expression of the BLM gene in human haematopoietic cells"Clin. Exp. Immunol.. 118. 285-289 (1999)
• [Publications] Tashita H, Kondo N, et al.: "Molecular basis of selective IgG2 deficiency : The mutated membrane-bound form of γ2 heavy chain caused complete IgG2 deficiency in two Japanese siblings"J. Clin. Invest.. 101. 677-681 (1998)
• [Publications] Kondo N, et al.: "Reduced interferon gamma production by antigen stimulated cord blood monomuclear cells is a risk factor allergic disorders. -6-year follow-up study"Clin. Exp. Allergy. 28. 1340-1344 (1998)
• [Publications] Orii Ke, Kondo N, et al.: "Genes for the human mitochondrial trifunctional protein α-and β-subunits are divergently transcribed from a common promoter region"J. Biol. Chem.. 274. 8077-8084 (1999)
• [Publications] Fukao T, Kondo N, et al.: "ATM is upregulated during the mitogenic response in peripheral blood mononuclear cells"Blood. 94. 1998-2006 (1999)
• [Publications] Matsui E, Kondo N, et al.: "Mutations of the IL-12 receptor β2 chain gene in some atopic subjects"Biochem. Biophy. Res. Commun.. 266. 551-555 (1999)
• [Publications] 近藤直実: "現代内科学:原発性免疫不全症候群 (1)抗体不全を主とする疾患"金芳堂. 2384 (1997)
• [Publications] 近藤直実: "分子アレルギー学:アトピーとIgE遺伝子"メディカルレビュー社. 599 (1998)
• [Publications] Kondo N et al: "Cord blood lymphoeyce responses to antigens for the piediction of allergy." Pedintric Asthma Allergy & Immunology. 12. 61-66 (1998)
• [Publications] Kondo N et al: "DNase I hypersensitive sites in himan I E region of lmmunolobulin heavy chain genes abnomally induced by interleuking in B lymphocytes of atopic pattenu with high levels of scrum IgE." J Invest Allergol & Clin Immunol. 8. 234-238 (1998)
• [Publications] Kaneko H, Kondo N et al: "BLM (the causative gene of Bloom syndrome) protein translocation into the nucleus by a nuclear lacalisation signal." Biochem Biophysical Res Commun. 240. 348-353 (1997)
• [Publications] Tashita H, Kondo N et al: "Molecular basis of selective IgG2 deficiency : The mutatid membrane-bound form of γ2 heavy chain caused complete IgG2 deficiency in two Japanese siblings." J Clin Invest. 101. 677-681 (1998)
• [Publications] Fukao T, Kondo N et al: "Ataria telangiectasia in the Japanese population : identification of R1917X,W2991R,R2909G,IVS33+2T+A,and 788 dets,the latter two being relatively common mutations." Hum Mutat. 12. 338-343 (1998)
• [Publications] Kondo N et al: "Reduced interferon gamma production by antigen stimulated cord blood mononuclear cells is a risk factor of allergic disorders-6-year follow-up study." Clin Exp Allergy. 28. 1340-1344 (1998)
• [Publications] 近藤直実: "現代内科学:原発性免疫不全症候群(1)抗体不全を主とする疾患" 金芳堂, 2384 (1997)
• [Publications] 近藤直実: "分子アレルギー学:アトピーとIgE遺伝子" メディカルレビュー社, 599 (1998)