Mechanisms of the induction of A:T mutations in the germinal center B cells

• Project/Area Number: 22590445
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Immunology
• Research Institution: The Institute of Physical and Chemical Research
• Principal Investigator: WANG Jiyang 独立行政法人理化学研究所, 免疫多様性研究チーム, チームリーダー (80231041)
• Co-Investigator(Kenkyū-buntansha): OUCHIDA Rika 独立行政法人理化学研究所, 免疫多様性研究チーム, 研究員 (80391887)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2012: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2011: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2010: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 胚中心B細胞 / 抗体遺伝子 / 体細胞変異 / ミスマッチ修復 / 細胞分裂 / 胚中心Ｂ細胞 / Uracil DNA glycosylase / DNA polymerase η / DNAポリメラーゼ / DNA修復

Research Abstract

The activation-induced cytidine deaminase converts cytosine to uracil and generates a U:G lesion on DNA, which obviously can cause mutations at the C:G pair. However, half of the mutations in the germinal center B cells occur at the non-damaged A:T pair. In the present study, we found that the induction of A:T mutations is an intrinsic property of the germinal center B cells and is independent of target gene location but requires rapid cell division.

Research Products

• [Journal Article] FcμR (Toso/Faim3) is not an inhibitor of Fas-mediated cell death in mouse T and B cells (2013)
  • Author(s): Ouchida, R., Mori, H., Ohno, H. and Wang, J.-Y.
  • Journal Title: Blood Volume: 121 Issue: 12 Pages: 2368-2370
  • DOI: 10.1182/blood-2012-12-470906
  • Peer Reviewed
• [Journal Article] High levels of AID cause strand bias of mutations at A versus T in Burkitt's lymphoma cells (2013)
  • Author(s): Kano, C. and Wang, J.-Y.
  • Journal Title: Mol. Immunol. Volume: 54 Issue: 3-4 Pages: 397-402
  • DOI: 10.1016/j.molimm.2013.01.005
  • Peer Reviewed
• [Journal Article] ADAR1 induces adenosine-targeted DNA mutations in senescent Bcl6-deficient cells (2013)
  • Author(s): Tsuruoka, N., Arima, M., Yoshida, N., Okada, S., Sakamoto, A., Hatano, M., Satake, H., Arguni, E., Wang, J.-Y., Yang, J.-H., Nishikura, K., Sekiya, S., Shozu, M. and Tokuhisa, T.
  • Journal Title: J. Biol. Chem. Volume: 288 Issue: 2 Pages: 826-836
  • DOI: 10.1074/jbc.m112.365718
  • Peer Reviewed
• [Journal Article] Analysis of Ig gene hypermutation in Ung~<-/->Polh^<-/-> mice suggests that UNG and A:T mutagenesis pathway target different U:G lesions (2013)
  • Author(s): Li, S., Zhao, Y. and Wang, J.-Y.
  • Journal Title: Mol. Immunol. Volume: 53 Issue: 3 Pages: 214-217
  • DOI: 10.1016/j.molimm.2012.08.009
  • Peer Reviewed
• [Journal Article] Critical role of the IgM Fc receptor in IgM homeostasis, B cell survival and humoral immune responses (2012)
  • Author(s): Ouchida, R., Mori, H., Hase, K., Takatsu, H., Kurosaki, T., Tokuhisa, T., Ohno, H., Wang. J. -Y.
  • Journal Title: Proc. Natl. Acad. Sci. USA Volume: 109 Issue: 40 Pages: 2699-2706
  • DOI: 10.1073/pnas.1210706109
  • Peer Reviewed
• [Journal Article] A novel mechanism for the autonomous termination of pre-B cell receptor expression via induction of lysosomal-associated protein transmembrane 5. (2012)
  • Author(s): Yohei Kawano
  • Journal Title: Molecular and Cellular Biology Volume: 32 Issue: 21 Pages: 4462-4471
  • DOI: 10.1128/mcb.00531-12
  • Peer Reviewed
• [Journal Article] LAPTM5 is a positive regulator of pro-inflammatory signaling pathways in macrophages (2012)
  • Author(s): Glowacka, W.K., Alberts, P., Ouchida, R., Wang, J.-Y. and Rotin, D.
  • Journal Title: J. Biol. Chem. Volume: 287 Issue: 33 Pages: 27691-27702
  • DOI: 10.1074/jbc.m112.355917
  • Peer Reviewed
• [Journal Article] HSP90α deficiency does not affect Ig gene hypermutation and class switch but causes enhanced MHC class II antigen presentation (2012)
  • Author(s): Li, Y., Li, S., Hoshino, M., Ishikawa, R., Kajiwara, C., Gao, X., Zhao, Y., Ishido, S., Udono, H., Wang, J. -Y.
  • Journal Title: Int. Immunol. Volume: 24 Issue: 12 Pages: 751-758
  • DOI: 10.1093/intimm/dxs076
  • Peer Reviewed
• [Journal Article] CD40 amplifies Fas-mediated apoptosis: a mechanism contributing to emphysema (2012)
  • Author(s): Shigeta, A., Tada, Y., Wang, J.-Y., Ishizaki, S., Tuyusaki, J., Yamauchi, K., Kasahara, Y., Iesato, K., Tanabe, N., Takiguchi, Y., Sakamoto, A., Tokuhisa, T., Shibuya, K., Hiroshima, K., West, J. and Tatsumi, K.
  • Journal Title: American Journal of Physiology Volume: 303 Issue: 2 Pages: 141-151
  • DOI: 10.1152/ajplung.00337.2011
  • Peer Reviewed
• [Journal Article] Analysis of mice deficient in both REV1 catalytic activity and POLH reveals an unexpected role for POLH in the generation of C to G and G to C transversions during Ig gene hypermutation. (2012)
  • Author(s): Kano C
  • Journal Title: Int Immunol Volume: 24 Issue: 3 Pages: 169-174
  • DOI: 10.1093/intimm/dxr109
  • Peer Reviewed
• [Journal Article] HSP90 contributes to cytosolic translocation of extracellular antigen for cross-presentation by dendritic cells. (2011)
  • Author(s): Imai T, Kato Y, Kajiwara C, Mizukami S, Ishige I, Ichiyanagi T, Hikida M, Wang JY, Udono H.
  • Journal Title: Proc. Natl. Acad. Sci. USA Volume: 108 Issue: 39 Pages: 16363-16368
  • DOI: 10.1073/pnas.1108372108
  • Peer Reviewed
• [Journal Article] Comparison of two POLQ mutants reveals that a polymerase-inactive POLQ retains significant function in tolerance to etoposide and γ-irradiation in mouse B cells (2011)
  • Author(s): Li, Y., Gao, X. and Wang, J.-Y.
  • Journal Title: Genes Cells Volume: 16 Issue: 9 Pages: 973-983
  • DOI: 10.1111/j.1365-2443.2011.01550.x
  • Peer Reviewed
• [Journal Article] Rapid cell division contributes to efficient induction of A/T mutations during Ig gene hypermutation (2011)
  • Author(s): Kano C, Ouchida R, Kokubo T, Wane JY
  • Journal Title: Molecular Immunology Volume: 48(15-16) Issue: 15-16 Pages: 1993-1999
  • DOI: 10.1016/j.molimm.2011.06.218
  • Peer Reviewed
• [Journal Article] Defining the immunological phenotype of Fc receptor-like B (FCRLB) deficient mice: confounding role of the inhibitory FcγRIIb(Featured in "In This Issue") (2010)
  • Author(s): Masuda, K., Mori, H., Ohara, O., Nakayama, M., Wang, J.-Y. and Burrows, P.
  • Journal Title: Cell. Immunol. Volume: 266 Issue: 1 Pages: 24-31
  • DOI: 10.1016/j.cellimm.2010.08.007
  • Peer Reviewed
• [Journal Article] A role for lysosomal-associated protein transmembrane 5 in the negative regulation of surface BCR levels and B cell activation (2010)
  • Author(s): Ouchida, R., Kurosaki, T. and Wang, J.-Y.
  • Journal Title: J. Immunol. Volume: 185 Issue: 1 Pages: 294-301
  • DOI: 10.4049/jimmunol.1000371
  • Peer Reviewed
• [Journal Article] Identification of TOSO/FAIM3 as an Fc receptor for IgM (2010)
  • Author(s): Shima, H., Takatsu, H., Fukuda, S., Ohmae, M., Hase, K., Kubagawa, H., Wang, J.-Y., and Ohno, H.
  • Journal Title: Int. Immunol. Volume: 22 Issue: 3 Pages: 149-156
  • DOI: 10.1093/intimm/dxp121
  • Peer Reviewed
• [Journal Article] Defining the immunological phenotype of Fc receptor-like B(FCRLB)deficient mice : confounding role of the inhibitory FcγRIIb. (2010)
  • Author(s): Masuda, K., Mori, H., Ohara, O., Nakayama, M., Wang J.-Y., Burrows, P.
  • Journal Title: Cell.Immunol. Volume: 266 Pages: 24-31
  • Peer Reviewed
• [Journal Article] A role for lysosomal-associated protein transmembrane 5 in the negative regulation of surface BCR levels and B cell activation. (2010)
  • Author(s): Ouchida, R., Kurosaki, T., Wang, J.-Y.
  • Journal Title: J.Immunol. Volume: 185 Pages: 294-301
  • Peer Reviewed
• [Journal Article] Analysis of mice deficient in both REV1 catalytic activity and POLH reveals an unexpected role for POLH in the generation of C to G and G to C transversions during Ig gene hypermutation
  • Author(s): Kano C, Hanaoka F, Wang J-Y
  • Journal Title: Int.Immunol. Volume: (in press)
  • Peer Reviewed
• [Presentation] Critical role of the IgM Fc receptor in IgM homeostasis (2012)
  • Author(s): Wang J-Y
  • Organizer: B cell survival and humoral immune responses International Symposium of the Japanese Society of Immunology
  • Place of Presentation: Kobe, Japan
  • Year and Date: 2012-12-06
• [Presentation] The IgM Fc receptor positively regulates B cell survival and antibody production (2012)
  • Author(s): Wang J-Y
  • Organizer: Innovation Summit Tokyo 2012 - Chronic Inflammation and Autoimmune Diseases
  • Place of Presentation: Tokyo
  • Year and Date: 2012-04-17
• [Presentation] The Fc receptor for IgM (FcμR) positively regulates primary and memory B cell responses (2012)
  • Author(s): Ouchida R, Mori H, Hase K, Kurosaki T, Ohno H, Wang J-Y
  • Organizer: Keystone Symposium on Regulation of Lymphocyte Signaling
  • Place of Presentation: Keystone, USA
  • Year and Date: 2012-03-13
• [Presentation] Critical role of the IgM Fc receptor in IgM homeostasis, B cell survival and humoral immune responses (2012)
  • Author(s): Wang, J.-Y.
  • Organizer: International Symposium of the Japanese Society of Immunology
  • Place of Presentation: Kobe
  • Invited
• [Presentation] The Fc receptor for IgM (FcμR) positively regulates B cell survival and activation (2011)
  • Author(s): Wang J-Y
  • Organizer: International Symposium of the Japanese Society of Immunology
  • Place of Presentation: Chiba, Japan
  • Year and Date: 2011-11-27
• [Presentation] The Fc receptor for IgM (FcμR) positively regulates B cell survival and activation (2011)
  • Author(s): 王継揚
  • Organizer: 第40回日本免疫学会総会学術集会
  • Place of Presentation: 幕張メッセ(千葉市)(招待講演)
  • Year and Date: 2011-11-27
• [Presentation] A critical role for REV1 in induction of C:G transitions and A:T mutations during immunoglobulin gene hypermutation (2010)
  • Author(s): Masuda K, Li Y, Ouchida R, Mori H, Wang J-Y
  • Organizer: 14^<th> International Congress of Immunology
  • Place of Presentation: Kobe, Japan
  • Year and Date: 2010-08-26
• [Presentation] Induction of A:T mutations is dependent on cellular environment but independent of mutation frequency and target gene location (2010)
  • Author(s): Kano C, Ouchida R, Moritan T, Wang J-Y
  • Organizer: 14^<th> International Congress of Immunology
  • Place of Presentation: Kobe, Japan
  • Year and Date: 2010-08-26
• [Presentation] Identification and characterization of the elusive IgM Fc receptor (FcμR) (2010)
  • Author(s): Kubagawa H, Oka S, Kubagawa Y, Torii I, Takayama E, Kang D, Gartland GL, Bertoli L, Mori H, Takatsu H, Kitamura T, Ohno H, Wang J-Y
  • Organizer: 14^<th> International Congress of Immunology
  • Place of Presentation: Kobe, Japan
  • Year and Date: 2010-08-25
• [Presentation] Identification of TOSO/FAIM3 as an Fc receptor for IgM (2010)
  • Author(s): Shima H, Takatsu H, Fukuda S, Ohmae M, Hase K, Kubagawa H, Wang J, Ohno H
  • Organizer: 14^<th> International Congress of Immunology
  • Place of Presentation: Kobe, Japan
  • Year and Date: 2010-08-25
• [Presentation] The autonomous termination of pre-BCR expression through BLNK-mediated induction of LAPTM5 (2010)
  • Author(s): Kawano Y, Ouchida R, Wang J, Yoshikawa S, Yamamoto M, Kitamura D, Karasuyama H
  • Organizer: 14^<th> International Congress of Immunology
  • Place of Presentation: Kobe, Japan
  • Year and Date: 2010-08-24
• [Presentation] A transcription factor regulates apoptosis of germinal center B cells and the production of high-affinity antibodies (2010)
  • Author(s): Li Y, Ouchida R, Wang J-Y
  • Organizer: 14^<th> International Congress of Immunology
  • Place of Presentation: Kobe, Japan
  • Year and Date: 2010-08-24
• [Presentation] The lysosomal protein LAPTM5 negatively regulates B cell activation and antibody production by downmodulating cell surface BCR expression (2010)
  • Author(s): Ouchida R, Mori H, Wang J-Y
  • Organizer: 14^<th> International Congress of Immunology
  • Place of Presentation: Kobe, Japan
  • Year and Date: 2010-08-23
• [Presentation] Induction of A:T mutations is dependent on cellular environment but independent of target gene location. (2010)
  • Author(s): Wang J, Kano C
  • Organizer: Experimental Biology
  • Place of Presentation: Anaheim, USA
  • Year and Date: 2010-04-28
• [Presentation] Induction of A : T mutations is dependent on cellular environment but independent of target gene location (2010)
  • Author(s): Wang, J.-Y., Kano C.
  • Organizer: Experimental Biology 2010
  • Place of Presentation: USA, Anaheim
  • Year and Date: 2010-04-28
• [Presentation] LAPTM5 controls B cell antigen receptor levels and negatively regulates B cell activation (2010)
  • Author(s): Ouchida R, Wang J-Y
  • Organizer: Keystone Symposium on Lymphocyte Activation and Gene Expression
  • Place of Presentation: Breckenridge, USA
  • Year and Date: 2010-03-01
• [Presentation] The lysosomal protein LAPTM5 negatively regulates B cell activation and antibody production by downmodulating cell surface BCR expression (2010)
  • Author(s): Ouchida, R., Wang, J.-Y.
  • Organizer: 14^<th> International Congress of Immunology
  • Place of Presentation: 神戸
• [Presentation] Induction of A : T mutations is dependent on cellular environment but independent of mutation frequency and target gene location (2010)
  • Author(s): Kano C., Ouchida, R., Moritan T., Wang, J.-Y.
  • Organizer: 14^<th> International Congress of Immunology
  • Place of Presentation: 神戸
• [Presentation] A transcription factor regulates apoptosis of germinal center B cells and the production of high-affinity antibodies (2010)
  • Author(s): Li Y., Ouchida, R., Wang, J.-Y.
  • Organizer: 14^<th> International Congress of Immunology
  • Place of Presentation: 神戸
• [Presentation] A critical role for REV1 in induction of C : G transitions and A : T mutations during immunoglobulin gene hypermutation (2010)
  • Author(s): Masuda K., Li Y., Ouchida, R.Mori H., Wang, J.-Y.
  • Organizer: 14^<th> International Congress of Immunology
  • Place of Presentation: 神戸
• [Remarks]
  • URL: http://web.rcai.riken.jp/en/labo/antigen/cv.html
• [Remarks]
  • URL: http://www.riken.go.jp/r-world/research/lab/rcai/antigen/index.html