Functional analysis of ubiquitin ligase RNF126

• Project/Area Number: 17K10432
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Radiation science
• Research Institution: Tohoku University
• Principal Investigator: Ishida Noriko 東北大学, 東北メディカル・メガバンク機構, 助教 (10361073)
• Co-Investigator(Kenkyū-buntansha): 中川 直 山陽小野田市立山口東京理科大学, 薬学部, 講師 (30707013)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: DNA損傷修復 / ユビキチン / E3リガーゼ / タンパク分解 / ノックアウトマウス / ユビキチンリガーゼ / 放射線 / ゲノム / 蛋白質分解 / DNA修復

Outline of Final Research Achievements

It was reported that E3 ligase RNF126 ubiquitinates Ku80, which plays an important role in DSB repair, and promotes the completion of repair (Ishida N et al. Mol Cell Biol. 2017; 37: e00347-16).
As a result of producing and analyzing RNF126 knockout (KO) mice, a decrease in T cells and sperm was observed. It was also confirmed that the phenotype obtained using the human cell line can be reproduced in KO mouse primary cells. Furthermore, as a result of producing and analyzing RNF126 CKO mice, it was clarified that RNF126 plays an important role in germ cell development in the testis.

Academic Significance and Societal Importance of the Research Achievements

ヒト細胞における、DNA損傷修復に重要なKu複合体を分解制御する新たな因子RNF126を発見・論文報告したことにより、DNA修復の二重鎖切断修復メカニズムの理解に貢献できた。また、RNF126のマウス個体レベルでの機能、T細胞や精子細胞分化における重要性を明らかにしたことより、T細胞維持や精子形成におけるユビキチンリガーゼやタンパク分解の理解に貢献できる可能性に繋がった。

Research Products

• [Journal Article] Landscape of electrophilic and inflammatory stress-mediated gene regulation in human lymphoblastoid cell lines (2020)
  • Author(s): Ishida Noriko、Aoki Yuichi、Katsuoka Fumiki、Nishijima Ichiko、Nobukuni Takahiro、Anzawa Hayato、Bin Li、Tsuda Miyuki、Kumada Kazuki、Kudo Hisaaki、Terakawa Takahiro、Otsuki Akihito、Kinoshita Kengo、Yamashita Riu、Minegishi Naoko、Yamamoto Masayuki
  • Journal Title: Free Radical Biology and Medicine Volume: 161 Pages: 71-83
  • DOI: 10.1016/j.freeradbiomed.2020.09.023
  • Peer Reviewed / Open Access
• [Journal Article] The Autism-Related Protein SETD5 Controls Neural Cell Proliferation through Epigenetic Regulation of rDNA Expression. (2020)
  • Author(s): Nakagawa T, Hattori S, Nobuta R, Kimura R, Nakagawa M, Matsumoto M, Nagasawa Y, Funayama R, Miyakawa T, Inada T, Osumi N, Nakayama KI, Nakayama K.
  • Journal Title: iScience Volume: 23 Issue: 4 Pages: 101030-101030
  • DOI: 10.1016/j.isci.2020.101030
  • Peer Reviewed / Open Access
• [Journal Article] A multi-ethnic meta-analysis identifies novel genes, including ACSL5, associated with amyotrophic lateral sclerosis. (2020)
  • Author(s): Nakamura R, Misawa K, Tohnai G, Nakatochi M, Furuhashi S, Atsuta N, Hayashi N, Yokoi D, Watanabe H, Watanabe H, Katsuno M, Izumi Y, Kanai K, Hattori N, Morita M, Taniguchi A, Kano O, Oda M, Shibuya K, Kuwabara S, Suzuki N, Aoki M, Ohta Y, Yamashita T, Abe K, Hashimoto R, Aiba I, Okada Y, Nagasaki M, Sobue G. et al.,
  • Journal Title: Commun Biol. Volume: 23 Issue: 1 Pages: 526-526
  • DOI: 10.1038/s42003-020-01251-2
  • NAID: 120007178464
  • Peer Reviewed / Open Access
• [Journal Article] Identification of Dominant Transcripts in Oxidative Stress Response by a Full-Length Transcriptome Analysis (2020)
  • Author(s): Otsuki Akihito、Okamura Yasunobu、Aoki Yuichi、Ishida Noriko、Kumada Kazuki、Minegishi Naoko、Katsuoka Fumiki、Kinoshita Kengo、Yamamoto Masayuki
  • Journal Title: Molecular and Cellular Biology Volume: 41 Issue: 2 Pages: 1-18
  • DOI: 10.1128/mcb.00472-20
  • Peer Reviewed / Open Access
• [Journal Article] Knockout Mouse Models Provide Insight into the Biological Functions of CRL1 Components. (2020)
  • Author(s): Nakagawa T, Nakayama K, Nakayama KI.
  • Journal Title: Adv Exp Med Biol. Volume: 1217 Pages: 147-171
  • DOI: 10.1007/978-981-15-1025-0_10
  • ISBN: 9789811510243, 9789811510250
  • Peer Reviewed
• [Journal Article] An Amyotrophic Lateral Sclerosis-Associated Mutant of C21ORF2 Is Stabilized by NEK1-Mediated Hyperphosphorylation and the Inability to Bind FBXO3 (2020)
  • Author(s): Watanabe Y, Nakagawa T, Akiyama T, Nakagawa M, Suzuki N, Warita H, Aoki M, Nakayama K.
  • Journal Title: iScience Volume: 23 Issue: 9 Pages: 1-15
  • DOI: 10.1016/j.isci.2020.101491
  • Peer Reviewed / Open Access
• [Journal Article] USP15 suppresses tumor immunity via deubiquitylation and inactivation of TET2 (2020)
  • Author(s): Chen LL, Smith MD, Lv L, Nakagawa T, Li Z, Sun SC, Brown NG, Xiong Y, Xu YP.
  • Journal Title: Science Advances Volume: 6 Issue: 38 Pages: 1-13
  • DOI: 10.1126/sciadv.abc9730
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Longitudinal plasma amino acid profiling with maternal genomic background throughout human pregnancy (2020)
  • Author(s): M Shirota, D Saigusa, R Yamashita, Y Kato, M Matsumoto, J Yamagishi, N Ishida, K Kumada, Y Oe, H Kudo, J Yokozawa, Y Kuroki, I Motoike, F Katsuoka, M Nagasaki, S Koshiba, K Nakayama, O Tanabe, J Yasuda, S Kure, K Kinoshita, H Metoki, S Kuriyama, N Yaegashi, M Yamamoto, J Sugawara
  • Journal Title: Medical Mass Spectrometry Volume: 4 Pages: 36-49
  • NAID: 130007897968
  • Peer Reviewed
• [Journal Article] Longitudinal plasma amino acid profiling with maternal genomic background throughout human pregnancy (2020)
  • Author(s): Shirota M, Saigusa D, Yamashita R, Kato Y, Matsumoto M, Yamagishi J, Ishida N, Kumada K, Oe Y, Kudo H, Yokozawa J, Kuroki Y, Motoike I, Katsuoka F, Nagasaki M, Koshiba S, Nakayama K, Tanabe O, Yasuda J, Kure S, Kinoshita K, Metoki H, Kuriyama S, Yaegashi N, Yamamoto M, Sugawara J
  • Journal Title: Medical Mass Spectrometry Volume: in press
  • NAID: 130007897968
  • Peer Reviewed
• [Journal Article] Biobank Establishment and Sample Management in the Tohoku Medical Megabank Project (2019)
  • Author(s): Minegishi Naoko、Nishijima Ichiko、Nobukuni Takahiro、Kudo Hisaaki、Ishida Noriko、Terakawa Takahiro、Kumada Kazuki、Yamashita Riu、Katsuoka Fumiki、Ogishima Soichi、Suzuki Kichiya、Sasaki Makoto、Satoh Mamoru、Tohoku Medical Megabank Project Study Group、Yamamoto Masayuki
  • Journal Title: The Tohoku Journal of Experimental Medicine Volume: 248 Issue: 1 Pages: 45-55
  • DOI: 10.1620/tjem.248.45
  • NAID: 130007652672
  • ISSN: 0040-8727, 1349-3329
  • Peer Reviewed / Open Access
• [Journal Article] A low-frequency IL4R locus variant in Japanese patients with intravenous immunoglobulin therapy-unresponsive Kawasaki disease. (2019)
  • Author(s): Yuji Amano, Yohei Akazawa, Jun Yasud, Kazuhisa Yoshino, Katsuhiko Kojima, Norimoto Kobayashi, Satoshi Matsuzaki, Masao Nagasaki, Yosuke Kawai, Naoko Minegishi, Noriko Ishida, Noriko Motoki, Akira Hachiya, Yozo Nakazawa, Masayuki Yamamoto, Kenichi Koike, Toshikazu Takeshita
  • Journal Title: Pediatr Rheumatol Volume: 17 Issue: 1 Pages: 1-11
  • DOI: 10.1186/s12969-019-0337-2
  • NAID: 120007113478
  • Peer Reviewed / Open Access
• [Journal Article] Pathogenic mutations in the ALS gene CCNF cause cytoplasmic mislocalization of Cyclin F and elevated VCP ATPase activity. (2019)
  • Author(s): Yu Y, Nakagawa T, Morohoshi A, Nakagawa M, Ishida N, Suzuki N, Aoki M, Nakayama K.
  • Journal Title: Hum Mol Genet Volume: 28 Issue: 20 Pages: 3486-3497
  • DOI: 10.1093/hmg/ddz119
  • Peer Reviewed
• [Journal Article] Aberrant axon branching via Fos-B dysregulation in FUS-ALS motor neurons. (2019)
  • Author(s): Akiyama T, Suzuki N, Ishikawa M, Fujimori K, Sone T, Kawada J, Funayama R, Fujishima F, Mitsuzawa S, Ikeda K, Ono H, Shijo T, Osana S, Shirota M, Nakagawa T, et al.
  • Journal Title: EBioMedicine Volume: 45 Pages: 362-378
  • DOI: 10.1016/j.ebiom.2019.06.013
  • Peer Reviewed / Open Access
• [Journal Article] The ubiquitin ligase subunit β-TrCP in Sertoli cells is essential for spermatogenesis in mice. (2019)
  • Author(s): Morohoshi, A., Nakagawa, T., Nakano, S., Nagasawa, Y., Nakayama, K.
  • Journal Title: Dev Biol. Volume: 445 Issue: 2 Pages: 178-188
  • DOI: 10.1016/j.ydbio.2018.10.023
  • Peer Reviewed
• [Journal Article] Transforming Growth Factor β-Induced Proliferative Arrest Mediated by TRIM26-Dependent TAF7 Degradation and Its Antagonism by MYC. (2018)
  • Author(s): Nakagawa T, Hosogane M, Nakagawa M, Morohoshi A, Funayama R, Nakayama K.
  • Journal Title: Mol Cell Biol Volume: 38 Issue: 5
  • DOI: 10.1128/mcb.00449-17
  • Peer Reviewed
• [Journal Article] Ubiquitylation of Ku80 by RNF126 Promotes Completion of Nonhomologous End Joining-Mediated DNA Repair. (2017)
  • Author(s): Ishida N, Nakagawa T, Iemura SI, Yasui A, Shima H, Katoh Y, Nagasawa Y, Natsume T, Igarashi K, Nakayama K.
  • Journal Title: Mol Cell Biol Volume: 37 Issue: 4
  • DOI: 10.1128/mcb.00347-16
  • Peer Reviewed
• [Journal Article] Regulation of mitosis-meiosis transition by the ubiquitin ligase β-TrCP in male germ cells. (2017)
  • Author(s): Nakagawa T, Zhang T, Kushi R, Nakano S, Endo T, Nakagawa M, Yanagihara N, Zarkower D, Nakayama K.
  • Journal Title: Development Volume: 144 Pages: 4137-4147
  • DOI: 10.1242/dev.158485
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The SCFβ-TRCP E3 ubiquitin ligase complex targets Lipin1 for ubiquitination and degradation to promote hepatic lipogenesis. (2017)
  • Author(s): Shimizu K, Fukushima H, Ogura K, Lien EC, Nihira NT, Zhang J, North BJ, Guo A, Nagashima K, Nakagawa T, Hoshikawa S, Watahiki A, Okabe K, Yamada A, Toker A, Asara JM, Fukumoto S, Nakayama KI, Nakayama K, Inuzuka H, Wei W.
  • Journal Title: Sci Signal. doi: 10.1126/scisignal.aah4117. Volume: 10 Issue: 460 Pages: 1-15
  • DOI: 10.1126/scisignal.aah4117
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 自閉症関連タンパク質SETD5によるｒDNAのエピジェネティック制御を介した神経細胞の増殖促進 (2020)
  • Author(s): 中川 直、中山 啓子
  • Organizer: 第10回武田科学振興財団 薬科学シンポジウム
  • Int'l Joint Research
• [Presentation] The Evaluation of Genomic Identity of the Cell Specimens in the TMM Biobank (2019)
  • Author(s): Kazuki Kumada, Noriko Ishida, Yuichi Aoki, Hisaaki Kudo, Riu Yamashita, Takahiro Nobukuni, Ichiko Nishijima, Takahiro Terakawa, Kengo Kinoshita, Masayuki Yamamoto, Naoko Minegishi
  • Organizer: ISBER
  • Int'l Joint Research
• [Presentation] 知的障害・自閉症関連因子SETD5によるrDNAのエピジェネティック制御 (2019)
  • Author(s): 中川直, 中山啓子
  • Organizer: 第42回日本分子生物学会
  • Invited
• [Presentation] Processing, Storage and Management Systems of Cell Samples in TMM Biobank (2018)
  • Author(s): Noriko Ishida, Takahiro Nobukuni, Ichiko Nishijima, isaaki Kudo, Riu Yamashita, Takahiro Terakawa, Masayuki Yamamoto, Naoko Minegishi
  • Organizer: Europe Biobank Week, Oral presentation, Topic 4C: Quality Assessment and Management of Samples and Data
  • Int'l Joint Research
• [Presentation] ユビキチン化によるFACT複合体の機能制御 (2018)
  • Author(s): 中川 直、諸星 茜、中山 啓子
  • Organizer: 第41回日本分子生物学会年会、ワークショップ：ユビキチン on クロマチン
  • Invited
• [Presentation] Mutation of cyclin F may contribute to Amyotrophic Lateral Sclerosis pathogenesis by affecting VCP (2018)
  • Author(s): Yujiao Yu. Akane Morohoshi, Tadashi Nakagawa, Keiko Nakayama
  • Organizer: 第41回日本分子生物学会年会、ポスター発表
• [Remarks] 東北大学大学院医学系研究科 附属創生応用医学研究センター がん医学コアセンター 細胞増殖制御分野
  • URL: http://www.devgen.med.tohoku.ac.jp/result/ronbun/index.html