Molecular mechanisms for class switch recombination and somatic hypermutation of immunoglobulin genes

• Project/Area Number: 20590277
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Gifu University (2010); Kyoto University (2008-2009)
• Principal Investigator: NAGAOKA Hitoshi 岐阜大学, 医学系研究科, 教授 (20270647)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2010: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2009: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2008: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 遺伝子 / 核酸 / ゲノム / 免疫学 / 抗体遺伝子 / AID / 発現調節 / 体細胞突然変異 / クラススイッチ組換え / 免疫 / 発がん

Research Abstract

AID is the molecule central for Immunoglobulin gene alteration ; its activity is believed to be involved in tumorigenesis in various types of cells. We have analyzed the regulatory elements in/around Aicda, the gene for AID and have determined essential DNA regions for enhancer and silencer. Some factors that bind to these elements were confirmed by chromatin immunoprecipitation. We also found that Spt6, a histone chaperon, associates with AID and it is involved in class switch recombination of immunoglobulin gene. A C-terminus of AID required for the repairing step of the recombination. These findings provide an important insight for understanding the molecular mechanisms of AID in normal and abnormal situation that are essential for antibody diversity and tumorigenesis, respectively.

Research Products

• [Journal Article] The AID Dilemma : Infection, or Cancer (2012)
  • Author(s): Honjo, T., Kobayashi, M., Begum, N., Kotani, A., Sabouri, S., and Nagaoka, H.
  • Journal Title: Adv Cancer Res Volume: 113 Pages: 1-44
• [Journal Article] Imatinib mesylate directly impairs class switch recombination through downregulation of AID : its potential efficacy as an AID suppressor (2012)
  • Author(s): Kawamata, T., Lu, J., Sato, T., Tanaka, M., Nagaoka, H., Agata, Y., Toyoshima, T., Yokoyama, K., Oyaizu, N., Nakamura, N., Ando, K., Tojo, A., and Kotani, A.
  • Journal Title: Blood
  • Peer Reviewed
• [Journal Article] The AID Dilemma : Infection, or Cancer? (2012)
  • Author(s): Honjo, T, 他
  • Journal Title: Adv Cancer Res Volume: 113 Pages: 1-44
• [Journal Article] Activation-Induced Cytidine Deaminase Expression in CD4 T Cells is Associated with a Unique IL-10-Producing Subset that Increases with Age (2011)
  • Author(s): Qin, H., Suzuki, K., Nakata, M., Chikuma, S., Izumi, N., Thi Huong, L., Maruya, M., Fagarasan, S., Busslinger, M., Honjo, T., and Nagaoka, H.
  • Journal Title: PLoS One 6 Volume: e29141
  • NAID: 120003726138
  • Peer Reviewed
• [Journal Article] Histone chaperone Spt6 is required for class switch recombination but not somatic hypermutation (2011)
  • Author(s): Okazaki, I. M., Okawa, K., Kobayashi, M., Yoshikawa, K., Kawamoto, S., Nagaoka, H., Shinkura, R., Kitawaki, Y., Taniguchi, H., Natsume, T., Iemura, S., and Honjo, T.
  • Journal Title: Proc Natl Acad Sci USA Volume: 108 Pages: 7920-7925
  • NAID: 120003163668
  • Peer Reviewed
• [Journal Article] Activation-Induced Cytidine Deaminase Expression in CD4 T Cells is Associated with a Unique IL-10-Producing Subset that Increases with Age (2011)
  • Author(s): Qin, H., 他
  • Journal Title: PLoS One Volume: 6(12)(電子出版)
  • Peer Reviewed
• [Journal Article] Histone chaperone Spt6 is required for class switch recombination but not somatic hypermutation (2011)
  • Author(s): Okazaki, IM, 他
  • Journal Title: Proc Natl Acad Sci U S A Volume: 108(19) Pages: 7920-7925
  • Peer Reviewed
• [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., and Kitamura, T.
  • Journal Title: Leukemia Volume: 24 Pages: 1018-1024
  • Peer Reviewed
• [Journal Article] Preventing AID, a physiological mutator, from deleterious activation : regulation of the genomic instability that is associated with antibody diversity (2010)
  • Author(s): Nagaoka, H., Tran, T. H., Kobayashi, M., Aida, M., and Honjo, T.
  • Journal Title: Int Immunol Volume: 22 Pages: 227-235
  • NAID: 10027391988
• [Journal Article] B cell-specific and stimulation-responsive enhancers derepress Aicda by overcoming the effects of silencers (2010)
  • Author(s): Tran, T. H., Nakata, M., Suzuki, K., Begum, N. A., Shinkura, R., Fagarasan, S., Honjo, T., and Nagaoka, H.
  • Journal Title: Nat Immunol Volume: 11 Pages: 148-154
  • NAID: 120001741673
  • Peer Reviewed
• [Journal Article] Preventing AID, a physiological mutator, from deleterious activation : regulation of the genomic instability that is associated with antibody diversity (2010)
  • Author(s): Nagaoka, H., 他
  • Journal Title: Int Immunol Volume: 22(4) Pages: 227-235
  • NAID: 10027391988
• [Journal Article] AID-induced T-lymphoma or B-leukemia/lymphoma in a mouse BMT model (2010)
  • Author(s): Komeno, Y., 他
  • Journal Title: Leukemia Volume: 24(5) Pages: 1018-1024
  • Peer Reviewed
• [Journal Article] B cell-specific and stimulation-responsive enhancers derepress Aicda by overcoming the effects of silencers. (2010)
  • Author(s): Tran, TH, 他
  • Journal Title: Nat Immunol Volume: 11 Pages: 148-154
  • Peer Reviewed
• [Journal Article] Preventing AID, a physiological mutator, from deleterious activation : regulation of the genomic instability that is associated with antibody diversity. (2010)
  • Author(s): Nagaoka, H, 他
  • Journal Title: Int Immunol Volume: 22 Pages: 227-235
  • NAID: 10027391988
• [Journal Article] AID-induced T-lymphoma or B-leukemia/lymphoma in a mouse BMT model. (2010)
  • Author(s): Komeno, Y, 他
  • Journal Title: Leukemia Volume: 24 Pages: 1018-1024
  • Peer Reviewed
• [Journal Article] Further evidence for involvement of a noncanonical 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., and Honjo, T.
  • Journal Title: Proc Natl Acad Sci USA Volume: 106 Pages: 2752-2757
  • Peer Reviewed
• [Journal Article] The C-terminal region of activation-induced cytidine deaminase is responsible for a recombination 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., and Honjo, T.
  • Journal Title: Proc Natl Acad Sci USA Volume: 106 Pages: 2758-2763
  • 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. M., Shinkura, R., Muramatsu, M., Kinoshita, K., and Honjo, T.
  • Journal Title: Proc Natl Acad Sci USA Volume: 106 Pages: 22375-22380
  • NAID: 120001749564
  • Peer Reviewed
• [Journal Article] Apex2 is required for efficient somatic hypermutation but not for class switch recombination of immunoglobulin genes (2009)
  • Author(s): Sabouri, Z., Okazaki, I. M., Shinkura, R., Begum, N., Nagaoka, H., Tsuchimoto, D., Nakabeppu, Y., and Honjo, T.
  • Journal Title: Int Immunol Volume: 21 Pages: 947-955
  • NAID: 10025387710
  • Peer Reviewed
• [Journal Article] Molecular mechanism for generation of antibody memory (2009)
  • Author(s): Shivarov, V., Shinkura, R., Doi, T., Begum, N. A., Nagaoka, H., Okazaki, I. M., Ito, S., Nonaka, T., Kinoshita, K., and Honjo, T.
  • Journal Title: Philos Trans R Soc Lond B Biol Sci Volume: 364 Pages: 569-575
  • Peer Reviewed
• [Journal Article] Apex2 is required for efficient somatic hypermutation but not for class switch recombination of immunoglobulin genes. (2009)
  • Author(s): Sabouri, Z, 他
  • Journal Title: Int Immunol Volume: 21 Pages: 947-955
  • 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, 他
  • Journal Title: Proc Natl Acad Sci U S A Volume: 106 Pages: 22375-22380
  • Peer Reviewed
• [Journal Article] Molecular mechanism for generation of antibody memory (2009)
  • Author(s): Shivarov, 他
  • Journal Title: Philos Trans R Soc Lond B Biol Sci 364 Pages: 569-75
• [Journal Article] The C-tsrminal region of activation-induced cytidine dearainase is responsible for a recombination function other than DNA cleavage in class switch recombination (2009)
  • Author(s): Doi, 他
  • Journal Title: Proc Natl Acad Sci USA 106 Pages: 2758-63
  • Peer Reviewed
• [Journal Article] Further evidence for involvement of a noncanonical function of uracil DNA glycosylase in class switch recombination (2009)
  • Author(s): Begum, 他
  • Journal Title: Proc Natl Acad Sci USA 106 Pages: 2752-7
  • Peer Reviewed
• [Journal Article] Imatinib mesylate directly impairs class switch recombination through downregulation of AID : its potential efficacy as an AID suppressor
  • Author(s): Kawamata, T, 他
  • Journal Title: Blood Volume: (On line先行)
  • Peer Reviewed
• [Presentation] AID遺伝子が発現するT細胞サブセットはIL-10を発現し加齢とともに蓄積するユニークなサブセットである (2011)
  • Author(s): 長岡仁, 他
  • Organizer: 第84回日本生化学会大会
  • Place of Presentation: 京都市
  • Year and Date: 2011-09-24
• [Presentation] RNF8によるPlk1タンパク質の減少とがん細胞における異常 (2011)
  • Author(s): 吉岡孝, 他
  • Organizer: 第84回日本生化学会大会
  • Place of Presentation: 京都市
  • Year and Date: 2011-09-22
• [Presentation] RNF8によるP1k1タンパク質の減少とがん細胞における異常 (2011)
  • Author(s): 吉岡孝, 他
  • Organizer: 第84回日本生化学会大会
  • Place of Presentation: 京都市
  • Year and Date: 2011-09-22
• [Presentation] Transcriptional regulation of Aicda, encoding activation-induced cytidine deaminase (2010)
  • Author(s): 長岡仁, 他
  • Organizer: 第14回国際免疫学会議
  • Place of Presentation: 神戸市
  • Year and Date: 2010-08-26
• [Presentation] AID遺伝子(Aicda)の発現は、刺激反応性及びBリンパ球特異的な2つのエンハンサー領域とそれに拮抗するサイレンサーにより制御される (2009)
  • Author(s): Tran TH, 他
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 神戸市
  • Year and Date: 2009-10-23
• [Presentation] 免疫グロブリン遺伝子座のクラススイッチ組換えにおけるTopisomerase Iの関与 (2009)
  • Author(s): 小林牧, 他
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 神戸市
  • Year and Date: 2009-10-23
• [Presentation] 免疫グロブリン遺伝子座のクラススイッチ組換えにおけるTopisomerase Iの関与 (2009)
  • Author(s): 小林牧, 他
  • Organizer: 第2回日本生化学会大会
  • Place of Presentation: 神戸市
  • Year and Date: 2009-10-23
• [Presentation] AID遺伝子(Aicda)の発現は、刺激反応性及びB リンパ球特異的な2つのエンハンサー領域とそれに拮抗するサイレンサーにより制御される。 (2009)
  • Author(s): Thinh Huy Tran, 他
  • Organizer: 第2回日本生化学会大会
  • Place of Presentation: 神戸市
  • Year and Date: 2009-10-23
• [Presentation] Identification of functionally important elements regulating activation-induced cytidine deaminase gene expression (2008)
  • Author(s): Tran TH, 他
  • Organizer: 第38回日本免疫学会総会・学術集会
  • Place of Presentation: 京都市
  • Year and Date: 2008-12-01
• [Presentation] Insturctive roles of transcription factors in regulating AID gene expression and function (2008)
  • Author(s): Thinh Huy Tran, 他
  • Organizer: 第81回日本生化学会大会第31回日本分子生物学会年会合同大会
  • Place of Presentation: 神戸市
  • Year and Date: 2008-11-10
• [Remarks]
  • URL: http://www.med.gifu-u.ac.jp/labo/labo-j/molpathobiochem.html
• [Remarks]
  • URL: http://www.med.gifu-u.ac.jp/labo/labo-j/molpathobiochem.html
• [Remarks]
  • URL: http://www2.mfour.med.kyoto-u.ac.jp/