AID-dependent genetic alteration mechanism to generate antigen-specific antibodies

2009 Fiscal Year Final Research Report

• Project/Area Number: 17002015
• Research Category: Grant-in-Aid for Specially Promoted Research
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Kyoto University
• Principal Investigator: HONJO Tasuku Kyoto University, 医学研究科, 客員教授 (80090504)
• Co-Investigator(Kenkyū-buntansha): NISHIKORI Momoko 京都大学, 医学研究科, 助教 (60378635)
• Co-Investigator(Renkei-kenkyūsha): SHINKURA Reiko 長浜バイオ大学, バイオサイエンス部, 教授 (50362471) ; BEGUM Nasim 京都大学, 医学研究科, 准教授 (80362507) ; NAGAOKA Hitoshi 岐阜大学, 医学研究科, 教授 (20270647) ; CHON Il-Mi (岡崎 一美) 徳島大学, 疾患ゲノム研究センター, 助教 (50452339) ; KOBAYASHI Maki 京都大学, 医学研究科, 准教授 (20400690) ; DOI Tomomitsu 慶應大学, 医学研究科, 助教 (70437218)
• Project Period (FY): 2005 – 2009
• Keywords: クラススイッチ / 体細胞突然変異 / RNA編集 / ウラシルDNAグリコシラーゼ / 免疫沈降法 / マイクロアレイ法

Research Abstract

We found that AID down-modulates translation of topoisomerase (Top1). The reduction of Top1 induces aberrant DNA structure in transcribed S regions, resulting in irreversible cleavage by Top1. We propose that AID edits microRNA and edited microRNA down-modulates translation of Top1 mRNA. AID was shown to be expressed not only in lymphoma but also pathogen-induced tumors. We investigated the AID promoter and identified positive and negative regulatory elements, which may explain such AID induction. We examined DNA deamination hypothesis and obtained the following evidence against this hypothesis. 1) AID mutant without DNA deamination activity is proficient for CSR. 2) UNG mutants of the protein interaction domain with normal U removal activity lost CSR activity. 3) APE1 and APE2 deficiency did not reduce CSR.

Research Products

• [Journal Article] AID-induced T-lymphoma or B-leukemia/lymphoma in a mouse BMT model. (2010)
  • Author(s): Komeno, Y., Kitaura, J., Watanabe-Okochi, N., Kato, N., Oki, T., Nakahara, F., Harada, Y., Harada, H., Shinkura, R., Nagaoka, H., Hayashi, Y., Honjo, T., Kitamura, T.
  • Journal Title: Leukemia 24 Pages: 1018-1024
  • Peer Reviewed
• [Journal Article] B cell-specific and stimulation-responsive enhancers derepress the Aicda gene by overcoming the effects of silencers. (2010)
  • Author(s): Tran, T., Nakata, M., Suzuki, K., Begum, N.A., Shinkura, R., Fagarasan, S., Honjo, T., Nagaoka, H.
  • Journal Title: Nature Immunol. 11 Pages: 148-154
  • Peer Reviewed
• [Journal Article] AID-induced decrease in topoisomerase 1 induces DNA structural alteration and DNA cleavage for class switch recombination. (2009)
  • Author(s): Kobayashi, M., Aida, M., Nagaoka, H., Begum, N.A., Kitawaki, Y., Nakata, M., Stanlie, A., Doi, T., Kato, L., Okazaki, I., Shinkura R., Muramatsu, M., Kinoshita, K., Honjo, T.
  • Journal Title: Proc.Natl.Acad.Sci.USA 106 Pages: 22375-22380
  • Peer Reviewed
• [Journal Article] Apex2 is required for efficient somatic hypermutation but not for class switch recombination of immunoglobilin genes. (2009)
  • Author(s): Sabouri, Z., Okazaki, I., Shinkura, R., Begum, N.A., Nagaoka, H., Tsuchimoto, D., Nakabeppu, Y., Honjo, T.
  • Journal Title: Int.Immunol. 21 Pages: 947-955
  • Peer Reviewed
• [Journal Article] The C-terminal region of AID is responsible for a novel function other than DNA cleavage in class switch recombination. (2009)
  • Author(s): Doi, T., Kato, L., Ito, S., Shinkura, R., Wei, M., Nagaoka, H., Wang, J., Honjo, T.
  • Journal Title: Proc.Natl.Acad.Sci.USA 106 Pages: 2758-2763
  • Peer Reviewed
• [Journal Article] Further evidence for involvement of a non-canonical function of uracil DNA glycosylase in class switch recombination. (2009)
  • Author(s): Begum, N.A., Stanlie, A., Doi, T., Sasaki, Y., Jin, H.W., Kim, Y.S., Nagaoka, H., Honjo, T.
  • Journal Title: Proc.Natl.Acad.Sci.USA 106 Pages: 2752-2757
  • Peer Reviewed
• [Journal Article] Carboxy-terminal domain of AID required for its mRNA complex formation in vivo. (2009)
  • Author(s): Nonaka, T., Doi, T., Toyoshima, T., Muramatsu, M., Honjo, T., Kinoshita, K.
  • Journal Title: Natl.Acad.Sci.USA 106 Pages: 2747-2751
  • Peer Reviewed
• [Journal Article] Dissociation of in vitro DNA deamination activity and physiological functions of AID mutants. (2008)
  • Author(s): Shivarov, V., Shinkura, R., Honjo, T.
  • Journal Title: Proc.Natl.Acad.Sci.USA. 105 Pages: 15866-15871
  • Peer Reviewed
• [Journal Article] Nature Immunol.A memoir of AID, which engraves antibody memory on DNA. (2008)
  • Author(s): Honjo, T.
  • Journal Title: Nature Immunol. 9 Pages: 335-337
  • Peer Reviewed
• [Journal Article] Morse, HC 3rd, Nussenzweig, MC and Dalla-Favera, R.AID is required for germinal center-derived lymphomagenesis. (2008)
  • Author(s): Pasqualucci, L., Bhagat, G., Jankovic, M., Compagno, M., Smith, P., Muramatsu, M., Honjo, T.
  • Journal Title: Nat.Genet. 40 Pages: 108-112
  • Peer Reviewed
• [Journal Article] Role of AID in tumorigenesis. (2007)
  • Author(s): Okazaki, I., Kotani, A., Honjo, T.
  • Journal Title: Adv.Immunol. 94 Pages: 245-273
  • Peer Reviewed
• [Journal Article] Discovery of activation-induced cytidine deaminase, the engraver of antibody memory. (2007)
  • Author(s): Muramatsu, M., Nagaoka, H., Shinkura, R., Begum, N.A., Honjo, T.
  • Journal Title: Adv.Immunol. 94 Pages: 1-36
  • Peer Reviewed
• [Journal Article] Helicobacter pylori infection triggers aberrant expression of activation-induced cytidine deaminase in gastric epithelium. (2007)
  • Author(s): Matsumoto, Y., Marusawa, H., Kinoshita, K., Endo, Y., Kou, T., Morisawa, T., Azuma, T., Okazaki, I., Honjo, T., Chiba, T.
  • Journal Title: Nature Medicine 13 Pages: 470-476
  • Peer Reviewed
• [Journal Article] Requirement of non-canonical activity of uracil DNA glycosylase for class switch recombination. (2007)
  • Author(s): Begum, N.A., Izumi, N., Nishikori, M., Nagaoka, H., Shinkura, R., Honjo, T.
  • Journal Title: J.Biol.Chem. 282 Pages: 731-742
  • Peer Reviewed
• [Journal Article] AID to overcome the limitations of genomic information. (2005)
  • Author(s): Honjo, T., Nagaoka, H., Shinkura, R., Muramatsu, M.
  • Journal Title: Nature Immunol. 6 Pages: 655-661
  • Peer Reviewed
• [Presentation] Common properties between class switch and meiotic homologous recombination. (2010)
  • Author(s): 本庶佑
  • Organizer: Cold Spring Harbor Laboratory Meeting on "Gene Expression and Signaling in the Immune System"
  • Place of Presentation: New York, USA
  • Year and Date: 2010-04-24
• [Presentation] Molecular studies on generation of antibody memory. (2009)
  • Author(s): 本庶佑
  • Organizer: The International Symposium on Genomics and Medicine, The Fondation Jean Dausset-Centre d'Etude du Polymorphisme Humain (CEPH)
  • Place of Presentation: Paris, France
  • Year and Date: 2009-03-23
• [Presentation] Molecular mechanism for generation of antibody memory. (2008)
  • Author(s): 本庶佑
  • Organizer: 2008 Leskowitz Memorial Lecture at Tufts University School of Medicine
  • Place of Presentation: Boston, USA
  • Year and Date: 2008-09-24
• [Presentation] Molecular mechanism for antibody memory.The Heidelberger-Kabat Lecture (2007)
  • Author(s): 本庶佑
  • Organizer: the Dean's Lecture Series 2006-2007, Columbia University Medical Center
  • Place of Presentation: New York, USA
  • Year and Date: 2007-02-15
• [Presentation] AID for generation of antigen-induced immune diversity. (2006)
  • Author(s): 本庶佑
  • Organizer: Paul E. Lacy Lecturer at Washington University in St. Louis
  • Place of Presentation: Louis, USA
  • Year and Date: 2006-05-01
• [Presentation] AID, a central molecule of immune diversity. (2005)
  • Author(s): 本庶佑
  • Organizer: 日独免疫セミナー
  • Place of Presentation: Potsdam, Germany
  • Year and Date: 2005-09-18
• [Book] いのちとはなにか-幸福・ゲノム・病 (2009)
  • Author(s): 本庶佑
  • Total Pages: 154
  • Publisher: 岩波書店
• [Book] Role of AID in tumorigenesis.,Vol.94 (2007)
  • Author(s): Okazaki, I., Kotani, A. Honjo, T.
  • Total Pages: 245-273
  • Publisher: ELSEVIER, Adv. Immunol.
• [Book] Discovery of activation-induced cytidine deaminase, the engraver of antibody memory. Vol.94 (2007)
  • Author(s): Muramatsu, M., Nagaoka, H., Shinkura, R., Begum, N.A., Honjo, T.
  • Total Pages: 1-36
  • Publisher: ELSEVIER, Adv. Immunol.
• [Remarks] ホームページ等
  • URL: http://www2.mfour.med.kyoto-u.ac.jp/
• [Remarks]
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