Hunting and analysis of novel genes causing Fanconi anemia

• Project/Area Number: 15H01738
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Risk sciences of radiation and chemicals
• Research Institution: Kyoto University
• Principal Investigator: Takata Minoru 京都大学, 放射線生物研究センター, 教授 (30281728)
• Co-Investigator(Kenkyū-buntansha): 石合 正道 京都大学, 放射線生物研究センター, 准教授 (90298844) ; 佐藤 浩一 早稲田大学, 理工学術院, 次席研究員(研究院助教) (60708585)
• Co-Investigator(Renkei-kenkyūsha): Hosokawa Hiroshi 京都大学, 情報学研究科, 講師 (90359779) ; Maegawa Shingo 京都大学, 情報学研究科, 助教 (30467401)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥46,020,000 (Direct Cost: ¥35,400,000、Indirect Cost: ¥10,620,000); Fiscal Year 2017: ¥12,350,000 (Direct Cost: ¥9,500,000、Indirect Cost: ¥2,850,000); Fiscal Year 2016: ¥14,170,000 (Direct Cost: ¥10,900,000、Indirect Cost: ¥3,270,000); Fiscal Year 2015: ¥19,500,000 (Direct Cost: ¥15,000,000、Indirect Cost: ¥4,500,000)
• Keywords: ファンコニ貧血 / FA経路 / RFWD3 / ユビキチン化 / 原因遺伝子 / DNA損傷修復 / 相同組換え / ゼブラフィッシュ / ゲノムシーケンス / DNA修復 / モノユビキチン化 / 次世代シーケンサー / アレイCGH / 先天性骨髄不全

Outline of Final Research Achievements

We analyzed unclassified FA cases and found that many of them are caused by slicing defects in known FA genes that were not evident in whole exome sequencing. We also identified two siblings that carry biallelic mutations in an important DNA repair factor. In 20 Indian FA cases, we identified frequent specific FANCL mutations, which are very rare in other ethnic groups. We generated novel zebrafish FANCT or FANCD2 model that resulted in 100% male fish. In collaborative efforts with German group, we established mutations in RFWD3 gene encoding a E3 ubiquitin ligase causes FA phenotype and that its targets are critical homologous recombination regulators, RPA and RAD51.

Research Products

• [Int'l Joint Research] University of Wuruzburg(Germany)
• [Int'l Joint Research] National Institute of Immunohaematology(India)
• [Int'l Joint Research] National Institute of Health(米国)
• [Int'l Joint Research] National Institute of Immunohaematology(India)
• [Int'l Joint Research] University of Wurzburg(Germany)
• [Int'l Joint Research] National Institute of Aging(米国)
• [Int'l Joint Research] Nantional Institute of Immunohaematology(India)
• [Journal Article] Replication stress induces accumulation of FANCD2 at central region of large fragile genes. (2018)
  • Author(s): Okamoto Y, Iwasaki WM, Kugou K, Takahashi KK, Oda A, Sato K, Kobayashi W, Kawai H, Sakasai R, Takaori-Kondo A, Yamamoto T, Kanemaki MT, Taoka M, Isobe T, Kurumizaka H, Innan H, Ohta K, Ishiai M, Takata M.
  • Journal Title: Nucleic Acids Res. Volume: 46(6) Issue: 6 Pages: 2932-2944
  • DOI: 10.1093/nar/gky058
  • NAID: 120006488604
  • Peer Reviewed / Open Access
• [Journal Article] PARI regulates stalled replication fork proessing to maintain genome stability upon replication stress in mice (2017)
  • Author(s): Ayako L. Mochizuki, Ami Katanaya, Eri Hayashi, Mihoko Hosokawa, Emiko Moribe, Akira Motegi, Masamichi Ishiai,Minoru Takata, Gen Kondoh, Hitomi Watanabe, Norio Nakatsuji, and Shinichiro Chuma
  • Journal Title: Mol. Cell. Biol Volume: 37 (23) Issue: 23
  • DOI: 10.1128/mcb.00117-17
  • Peer Reviewed / Open Access
• [Journal Article] Biallelic mutations in the ubiquitin ligase RFWD3 cause Fanconi anemia. (2017)
  • Author(s): Kerstin Knies, Shojiro Inano, Maria Ramirez, Masamichi Ishiai, Jordi Suralles, Minoru Takata, and Detlev Schindler.
  • Journal Title: Journal of Clinical Investigation Volume: 127 Issue: 8 Pages: 3013-3027
  • DOI: 10.1172/jci92069
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] RFWD3-Mediated Ubiquitination Promotes Timely Removal of Both RPA and RAD51 from DNA Damage Sites to Facilitate Homologous Recombination (2017)
  • Author(s): Inano Shojiro、Sato Koichi、Katsuki Yoko、Kobayashi Wataru、Tanaka Hiroki、Nakajima Kazuhiro、Nakada Shinichiro、Miyoshi Hiroyuki、Knies Kerstin、Takaori-Kondo Akifumi、Schindler Detlev、Ishiai Masamichi、Kurumizaka Hitoshi、Takata Minoru
  • Journal Title: Molecular Cell Volume: 66 Issue: 5 Pages: 622-634
  • DOI: 10.1016/j.molcel.2017.04.022
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Common Variable Immunodeficiency Caused by FANC Mutations (2017)
  • Author(s): Sekinaka Y., Mitsuiki N., Imai K., Yabe M., Yabe H., Mitsui-Sekinaka K., Honma K., Takagi M., Arai A., Yoshida K., Okuno Y., Shiraishi Y., Chiba K., Tanaka H., Miyano S., Muramatsu H., Kojima S., Hira A., Takata M., Ohara O., Ogawa S., Morio T., Nonoyama S.
  • Journal Title: Journal of clinical immunology Volume: 37 Issue: 5 Pages: 434-444
  • DOI: 10.1007/s10875-017-0396-4
  • Peer Reviewed / Open Access
• [Journal Article] Clinical utility of next-generation sequencing for inherited bone marrow failure syndromes. (2017)
  • Author(s): Muramatsu H, Okuno Y, Yoshida K, Shiraishi Y, Doisaki S, Narita A, Sakaguchi H, Kawashima N, Wang X, Xu Y, Chiba K, Tanaka H, Hama A, Sanada M, Takahashi Y, Kanno H, Yamaguchi H, Ohga S, Manabe A, Harigae H, Kunishima S, Ishii E, Kobayashi M, Koike K, Watanabe K, Ito E, Takata M, Yabe M, Ogawa S, Miyano S, Kojima S.
  • Journal Title: Genet Med. Volume: - Issue: 7 Pages: 796-802
  • DOI: 10.1038/gim.2016.197
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Bloom syndrome complex promotes FANCM recruitment to stalled replication forks and facilitates both repair and traverse of DNA interstrand crosslinks. (2016)
  • Author(s): Chen Ling, Jing Huang, Zhijiang Yan, Yongjiang Li, Mioko Ohzeki, Masamichi Ishiai, Dongyi Xu, Minoru Takata, Michael Seidman, and Weidong Wang.
  • Journal Title: Cell Discov Volume: 2 Issue: 1 Pages: 16047-16047
  • DOI: 10.1038/celldisc.2016.47
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Homologous Recombination and Translesion DNA Synthesis Play Critical Roles on Tolerating DNA Damage Caused by Trace Levels of Hexavalent Chromium. (2016)
  • Author(s): Tian X, Patel K, Ridpath JR, Chen Y, Zhou YH, Neo D, Clement J, Takata M, Takeda S, Sale J, Wright FA, Swenberg JA, Nakamura J
  • Journal Title: PLoS One Volume: 11 Issue: 12 Pages: e0167503-e0167503
  • DOI: 10.1371/journal.pone.0167503
  • NAID: 120005980904
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] FANCI-FANCD2 stabilizes the RAD51-DNA complex by binding RAD51 and protects the 5'-DNA end. (2016)
  • Author(s): Sato K, Shimomuki M, Katsuki Y, Takahashi D, Kobayashi W, Ishiai M, Miyoshi H, Takata M, Kurumizaka H.
  • Journal Title: Nucleic Acids Res Volume: 44 Issue: 22 Pages: 10758-10771
  • DOI: 10.1093/nar/gkw876
  • NAID: 120006318854
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Defects in HR repair behind the human diseases: FA and HBOC. Endocrine Related Cancer. (2016)
  • Author(s): Katsuki Y, Takata M.
  • Journal Title: Endocrine Related Cancer. Volume: 23 Issue: 10 Pages: T19-T37
  • DOI: 10.1530/erc-16-0221
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Poor recognition of O6-isopropyl dG by MGMT triggers double strand break-mediated cell death and micronucleus induction in FANC-deficient cells. (2016)
  • Author(s): Hashimoto K, Sharma V, Sasanuma H, Tian X, Takata M, Takeda S, Swenberg JA, Nakamura J
  • Journal Title: Oncotarget Volume: 7 Issue: 37 Pages: 59795-59808
  • DOI: 10.18632/oncotarget.10928
  • NAID: 120005980805
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The phenotype and clinical course of Japanese Fanconi Anaemia infants is influenced by patient, but not maternal ALDH2 genotype. (2016)
  • Author(s): Yabe M, Yabe H, Morimoto T, Fukumura A, Ohtsubo K, Koike T, Yoshida K, Ogawa S, Ito E, Okuno Y, Muramatsu H, Kojima S, Matsuo K, Hira A, Takata M.
  • Journal Title: Br J Haematol. Volume: 175 Issue: 3 Pages: 457-461
  • DOI: 10.1111/bjh.14243
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Human FAN1 promotes strand incision in 5'-flapped DNA complexed with RPA. (2015)
  • Author(s): Takahashi D, Sato K, Hirayama E, Takata M, Kurumizaka H.
  • Journal Title: J Biochem Volume: 158 Issue: 3 Pages: 263-70
  • DOI: 10.1093/jb/mvv043
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Pluripotent cell models of Fanconi anemia identify the early pathological defect in human hemoangiogenic progenitors. (2015)
  • Author(s): Suzuki NM, Niwa A, Yabe M, Hira A, Okada C, Amano N, Watanabe A, Watanabe K, Heike T, Takata M, Nakahata T, Saito MK
  • Journal Title: Stem Cells Transl Med Volume: 4 Issue: 4 Pages: 333-338
  • DOI: 10.5966/sctm.2013-0172
  • NAID: 120005980869
  • Peer Reviewed / Open Access
• [Journal Article] Mutations in the gene encoding the E2 conjugating enzyme UBE2T cause Fanconi anemia. (2015)
  • Author(s): Hira A, Yoshida K, Sato K, Okuno Y, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Shimamoto A, Tahara H, Ito E, Kojima S, Kurumizaka H, Ogawa S, Takata M, Yabe H, Yabe M.
  • Journal Title: Am J Hum Genet. Volume: 96(6) Issue: 6 Pages: 1001-7
  • DOI: 10.1016/j.ajhg.2015.04.022
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Rad18 and Rnf8 facilitate homologous recombination by two distinct mechanisms, promoting Rad51 focus formation and suppressing the toxic effect of nonhomologous end-joining (2015)
  • Author(s): Michael Schmid, Akira Motegi (ほか総計106名、代表者は前から63番目)
  • Journal Title: Cytogenet. Genome Res. Volume: 145 Issue: 2 Pages: 78-179
  • DOI: 10.1159/000430927
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Conserved overlapping gene arrangement, restricted expression and biochemical activities of DNA polymerase ν; (POLN). (2015)
  • Author(s): Takata KI, Tomida J, Reh S, Swanhart LM, Takata M, Hukriede NA, Wood RD.
  • Journal Title: J Biol Chem Volume: 290 Issue: 40 Pages: 27278-93
  • DOI: 10.1074/jbc.m115.677419
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Pathogenesis of Fanconi anemia: an update. (2017)
  • Author(s): Minoru Takata
  • Organizer: International Conference on “ Revolution of Laboratory Medicine In Modern Biology”
  • Place of Presentation: Mumbai, India
  • Year and Date: 2017-02-15
  • Int'l Joint Research / Invited
• [Presentation] ICL修復因子SLX4はRNF168依存的なユビキチン化経路を介して損傷部位に集積する. (2017)
  • Author(s): 勝木陽子, 安倍昌子, Haico van Attikum, 中田慎一郎, 鐘巻将人, Yonghwan Kim, 高田穣.
  • Organizer: 生命科学系学会合同年次大会ConBio2017, 第40回日本分子生物学会年会ワークショップ.
• [Presentation] Regulation of homologous recombination by a novel FA protein RFWD3/FANCW． (2017)
  • Author(s): Minoru Takata
  • Organizer: 1st International Symposium on Radiation Therapeutics and Biology (isRTB-2017)
  • Int'l Joint Research / Invited
• [Presentation] Regulation of homologous recombination repair by a novel Fanconi anemia E3 ligase RFWD3/FANCW. (2017)
  • Author(s): Minoru Takata
  • Organizer: 6th US-Japan DNA Repair Meeting, Clark-Kerr Campus, Berkeley, CA, USA.
  • Int'l Joint Research / Invited
• [Presentation] Regulation of homologous recombination by a novel FA protein RFWD3. (2017)
  • Author(s): Shojiro Inano, Koichi Sato, Yoko Katsuki, Kerstin Knies, Detlev Schindler, Masamichi Ishiai, Hitoshi Kurumizaka, Minoru Takata.
  • Organizer: FEBS workshop Nucleotide excision repair and crosslink repair - from molecules to mankind. Smolenice, Slovakia.
  • Int'l Joint Research / Invited
• [Presentation] A novel Fanconi anemia gene regulates ICL repair and homologous recombination. (2016)
  • Author(s): Minoru Takata
  • Organizer: 第58回日本小児血液・がん学会学術集会 シンポジウム
  • Place of Presentation: 品川プリンスホテル 東京
  • Year and Date: 2016-12-15
  • Invited
• [Presentation] 相同組換えにおけるRPAおよびRAD51の動態制御はRFWD3によるユビキチン化に依存する (2016)
  • Author(s): 稲野将二郎、佐藤浩一、勝木陽子、石合正道、中田慎一郎、胡桃坂仁志、高田 穣
  • Organizer: 第75回日本癌学会学術総会 シンポジウム
  • Place of Presentation: 横浜市パシフィコ横浜
  • Year and Date: 2016-10-06
• [Presentation] Novel Fanconi anemia E3 ligase RFWD3 promotes removal of both RPA and RAD51 from DNA damage sites during ICL repair. (2016)
  • Author(s): Shojiro Inano, Koichi Sato, Kerstin Knies, Yoko Katsuki, Shinichiro Nakada, Akifumi Takaori-Kondo, Masamicih Ishiai, Detlev Schindler, Hitoshi Kurumizaka, Minoru Takata.
  • Organizer: 28th Annual Fanconi Anemia research frund Scientific Symposium.
  • Place of Presentation: Bellevue, WA USA
  • Year and Date: 2016-09-15
  • Int'l Joint Research
• [Presentation] Myelodysplastic syndrome and acute myeloid leukemia in Japanese Fanconi anemia patients. (2016)
  • Author(s): Miharu Yabe, Tsuyoshi Morimoto, Akiko Fukumura, Keisuke Ohtsubo, Takashi Koike, Takashi Shimizu, Hiromitsu Takakura, Katsuyoshi Koh, Etsuro Ito, Seiji Kojima, Asuka Hira, Minoru Takata and Hiromasa Yabe.
  • Organizer: 28th Annual Fanconi Anemia research frund Scientific Symposium.
  • Place of Presentation: Bellevue, WA USA
  • Year and Date: 2016-09-15
  • Int'l Joint Research
• [Presentation] 相同組換えにおけるＲＰＡ２のユビキチン化を介した分解 (2015)
  • Author(s): 稲野将二郎、佐藤浩一、石合正道、勝木陽子、中田慎一郎、胡桃坂仁志、高田 穣
  • Organizer: BMB2015
  • Place of Presentation: 神戸ポートアイランド
  • Year and Date: 2015-12-01
  • Invited
• [Presentation] 複製ストレスによるFANCD2集積部位のゲノムワイド解析 (2015)
  • Author(s): 石合正道、岩嵜航、高橋数冴、久郷和人、小田有沙、大木千夏、福井哲也、河合秀彦、山本卓、太田邦史、印南秀樹、高田穣
  • Organizer: BMB2015
  • Place of Presentation: 神戸ポートアイランド
  • Year and Date: 2015-12-01
  • Invited
• [Presentation] UBE2T/FANCT is a novel FA gene identified in Japanese Fanconi anemia patients. (2015)
  • Author(s): Minoru Takata, Asuka Hira, Kenichi Yoshida, Koichi Sato, Akira Shimamoto, Hitoshi Kurumizaka, Seishi Ogawa, Hiromasa Yabe, and Miharu Yabe.
  • Organizer: The 16th Ataxia-Teleangiectasia Workshop.
  • Place of Presentation: Beijing China
  • Year and Date: 2015-10-11
  • Int'l Joint Research
• [Presentation] ファンコニ貧血と遺伝性乳がん卵巣がん：相同組換え欠損を基盤とした高発がん症候群 (2015)
  • Author(s): 高田 穰
  • Organizer: 第74回日本癌学会 学術総会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2015-10-08
  • Invited
• [Presentation] DNA damage and repair in Fanconi anemia (2015)
  • Author(s): Minoru Takata
  • Organizer: 第２回IFOM－京都大学合同シンポジウム
  • Place of Presentation: 京都大学紫蘭会館稲森ホール
  • Year and Date: 2015-10-06
  • Int'l Joint Research / Invited
• [Presentation] Mutations in the gene encoding the E2 conjugating enzyme UBE2T cause Fanconi anemia. (2015)
  • Author(s): Hira, K. Yoshida, K.Sato, Y. Shiraishi, K. Chiba, H. Tanaka, S. Miyano, A. Shimamoto, H.Tahara, E.Ito, S.Kojima, H. Kurumizaka, S.Ogawa, M.Takata, H.Yabe, M. Yabe.
  • Organizer: 27th Annual Fanconi anemia research fund Scientific Symposium.
  • Place of Presentation: Tronto, Canada
  • Year and Date: 2015-09-17
  • Int'l Joint Research
• [Presentation] Identification of UBE2T as a novel Fanconi anemia gene. (2015)
  • Author(s): Asuka Hira, Kenichi Yoshida, Koichi Sato, Akita Shimamoto, Hidetoshi Tahara, Hitoshi Kurumizaka, Seishi Ogawa, Minoru Takata, Hiromasa Yabe, Miharu Yabe.
  • Organizer: ICRR2015
  • Place of Presentation: Kyoto 国際会館
  • Year and Date: 2015-05-25
  • Int'l Joint Research
• [Book] 先天性骨髄不全症 診療ガイドライン2017． (2017)
  • Author(s): 矢部普正、高田穣、村松秀樹
  • Total Pages: 96
  • Publisher: 診断と治療社
  • ISBN: 9784787823311
• [Book] DNA Replication, Recombination, and Repair (2015)
  • Author(s): Masamichi Ishiai, Junya Tomida, Akiko Itaya, James Hejna, Minoru Takata.
  • Total Pages: 35
  • Publisher: Springer Japan
• [Remarks] 京都大学 放射線生物研究センター 晩発効果研究部門 ホームページ
  • URL: http://www.rbc.kyoto-u.ac.jp/late-effect
• [Remarks] 京都大学 放射線生物研究センター 一般の方へ
  • URL: http://www.rbc.kyoto-u.ac.jp/research
• [Remarks] 一般の方へ
  • URL: http://house.rbc.kyoto-u.ac.jp/research
• [Remarks] 放射線生物研究センター
  • URL: http://www.rbc.kyoto-u.ac.jp
• [Remarks] 研究成果アーカイブ
  • URL: http://house.rbc.kyoto-u.ac.jp/research