Tasuku Honjo, M.D., Ph.D. Professor
We have been studying molecular mechanisms controlling development and function of lymphocytes. Currently we are addressing two important questions: 1) How antibody diversity is controlled by AID, a putative RNA-editing enzyme required for class switch recombination (CSR) and somatic hypermutation (SHM), 2) How PD-1 deficiency leads to development of autoimmune diseases. We found that AID reduces the amount of Topoisomerase 1, generating non-B DNA and inducing irreversible cleavage by Topoisomearse 1.
Research and EducationIn 1978, we proposed and subsequently proved that class switch is mediated by recombination with dynamic excision of genomic fragments. In 2000, we discovered activation-induced cytidine deaminase (AID), which is responsible for DNA cleavage to initiate both CSR and SHM. Surprisingly, AID mutates not only the antibody gene, but also protooncogenes. We have recently found that topoisomerase 1 (Top1) is the enzyme that initiates CSR and SHM by cleaving S and V region, respectively. In addition, AID reduces the amount of Top1, inducing the target DNA structural change, which causes the irreversible cleavage by Top1. Furthermore, the transcription coupled nucleosomal reassembly is critical for this Top1-mediated DNA cleavage during CSR and SHM.
Recently, clinical trials of humanized anti-PD-1 antibody against melanoma, renal cancer and lung cancer proved this antibody treatment is very effective. PD-1 plays critical roles in anti-cancer immunity and autoimmunity. The aim of our research is to contribute to human welfare through regulation of immune responses, elucidation of tumorigenesis and its prevention by studying the function of AID and PD-1.
「Blockade of PD-1 pathway provides an effective immunotherapy for cancer」
「AID engrave antibody memory」
Recent Publications1. Muramatsu, M., Kinoshita, K., Fagarasan, S., Yamada, S., Shinkai, Y. and Honjo, T. “Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme.” Cell (2000) 102(5):553-63.
2. Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc. Natl. Acad. Sci. U S A. (2002) 99:12293-7.
3. 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. and Honjo, T. “AID-induced decrease in topoisomerase 1 induces DNA structural alteration and DNA cleavage for class switch recombination.” Proc. Natl. Acad. Sci. USA (2009) 106:22375-80.
4. Okazaki T, Chikuma S, Iwai Y, Fagarasan S, Honjo T. A rheostat for immune responses: the unique properties of PD-1 and their advantages for clinical application. Nat. Immunol. (2013) 14:1212-8.
5. Stanlie A, Yousif AS, Akiyama H, Honjo T, Begum NA. Chromatin reader Brd4 functions in Ig class switching as a repair complex adaptor of nonhomologous end-joining. Mol. Cell. (2014) 55:97-110.
LaboratoryProfessor Tasuku Honjo
Associate professor Nasim Begum ・ Kobayashi Maki
Assistant professor Shunsuke Chikuma
TEL +81-75-753-4371 FAX 、+81-75-753-4388