Analysis of tissue-specific distribution and function of ALDH isoforms in Fanconi anemia pathway

• Project/Area Number: 26550026
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• 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)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: アルデヒド / ALDH / ファンコニ貧血 / ALDH2 / ADH5 / 内因性アルデヒド / 再生不良性貧血 / DNA修復 / ＡＬＤＨ

Outline of Final Research Achievements

We have previously reported that Fanconi anemia (FA) patients with variant alleles of ALDH2 gene encoding an acetoaldehyde-catalyzing enzyme display accelerated progression of bone marrow failure, indicating that endogenous aldehydes damage DNA in hematopoietic stem cells and FA pathway is counteracting them. In this study, we have determined tissue specific mRNA expression of 19 ALDH isozymes in CD34+ progenitor cells, liver cells, and placenta cells. We also identified a set of Japanese patients who displayed bone marrow failure and had biallelic mutations in one of the alydehyde-catalyzing enzyme genes. This is probably a new syndrome that is caused by accumulated DNA damage due to lower catabolism of endogenous aldehydes.

Research Products

• [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 Pages: 1001-7
  • Peer Reviewed / Open Access
• [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
• [Journal Article] Defective FANCI Binding by a Fanconi Anemia-Related FANCD2 Mutant. (2014)
  • Author(s): Sato K, Ishiai M, Takata M, Kurumizaka H.
  • Journal Title: PLoS One Volume: 9 Issue: 12 Pages: e114752-e114752
  • DOI: 10.1371/journal.pone.0114752
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The Trp53-Trp53inp1-Tnfrsf10b Pathway Regulates the Radiation Response of Mouse Spermatogonial Stem Cells. (2014)
  • Author(s): Kei Ishii, Masamichi Ishiai, Hiroko Morimoto, Mito Kanatsu-Shinohara, Ohtsura Niwa, Minoru Takata, and Takashi Shinohara.
  • Journal Title: Stem Cell Reports. Volume: 3 Issue: 4 Pages: 676-89
  • DOI: 10.1016/j.stemcr.2014.08.006
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Modularized functions of the Fanconi anemia core complex. (2014)
  • Author(s): Huang Y, Leung JW, Lowery M, Matsushita N, Wang Y, Shen X, Huong D, Takata M, Chen J, Li L.
  • Journal Title: Cell Rep. Volume: 7 Issue: 6 Pages: 1849-57
  • DOI: 10.1016/j.celrep.2014.04.029
  • Peer Reviewed / Open Access
• [Journal Article] FANCD2 Binds CtIP and Regulates DNA-End Resection during DNA Interstrand Crosslink Repair. (2014)
  • Author(s): Unno J
  • Journal Title: Cell Rep. Volume: 7 Issue: 4 Pages: 1039-1047
  • DOI: 10.1016/j.celrep.2014.04.005
  • Peer Reviewed / Open Access
• [Journal Article] Tumor suppressor RecQL5 controls recombination induced by DNA crosslinking agents (2014)
  • Author(s): Yoshifumi Hosono, Takuya Abe, Masamichi Ishiai, M. Nurul Islam, Hiroshi Arakawa, Weidong Wang, Shunichi Takeda, Yutaka Ishii, Minoru Takata, Masayuki Seki, Takemi Enomoto
  • Journal Title: Biochimica et Biophysica Acta-Molecular Cell Research Volume: 1843 Issue: 5 Pages: 1002-1012
  • DOI: 10.1016/j.bbamcr.2014.01.005
  • Peer Reviewed / Open Access
• [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 ワークショップ
  • 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 ワークショップ
  • Place of Presentation: 神戸ポートアイランド
  • Year and Date: 2015-12-01
  • Invited
• [Presentation] Mutations in the gene encoding the E2 conjugating enzyme UBE2T cause Fanconi anemia. (2015)
  • Author(s): A. 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: 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 シンポ
  • 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): 高田 穰
  • 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): A. 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: The 27th Annual Fanconi anemia research fund Scientific Symposium.
  • Place of Presentation: Toronto, 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: 京都国際会館
  • Year and Date: 2015-05-25
  • Int'l Joint Research
• [Presentation] 日本人ファンコニ貧血患者における新規原因遺伝子UBE2Tの同定 (2014)
  • Author(s): 平 明日香, 吉田 健一, 佐藤 浩一, 嶋本 顕, 田原 栄俊, 胡桃坂 仁志, 小川 誠司, 高田 穣, 矢部 普正, 矢部 みはる
  • Organizer: 第37回日本分子生物学会年会 ワークショップ
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] ファンコニ貧血経路とそのキータンパク質FANCD2の機能解析 (2014)
  • Author(s): 高田 穣, 勝木 陽子, 佐藤 浩一, 石合 正道, 胡桃坂 仁志
  • Organizer: 第37回日本分子生物学会年会 ワークショップ
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-11-25 – 2014-11-27
  • Invited
• [Presentation] UBE2T is a novel FA gene identified in Japanese Fanconi anemia patients (2014)
  • Author(s): Minoru Takata, Asuka Hira, Kenichi Yoshida, Koichi Sato, Akira Shimamoto, Hidetoshi Tahara, Hitoshi Kurumizaka, Seishi Ogawa, Hiromasa Yabe, and Miharu Yabe
  • Organizer: The 9th 3R Symposium,
  • Place of Presentation: Gotemba Kogen Hotel
  • Year and Date: 2014-11-17 – 2014-11-21
• [Presentation] Comprehensive analysis of Japanese Fanconi anemia (FA) patients has led to the identification of an E2 enzyme UBE2T as a novel FA gene. (2014)
  • Author(s): Minoru Takata.
  • Organizer: 日米修復会議
  • Place of Presentation: エクシブ鳴門
  • Year and Date: 2014-10-29
  • Invited
• [Presentation] Infant Japanese Fanconi anemia patients with the ALDH2-AA genotype. (2014)
  • Author(s): M. Yabe, A. Hira, H, Yabe, T. Morimoto, A. Fukumura, M. Miyashita, K. Ohtsubo, K. Matsuo, M. Takata.
  • Organizer: 26th Annual Fanconi Anemia Research Fund Scientific Symposium.
  • Place of Presentation: Bethesda MA, USA
  • Year and Date: 2014-09-18 – 2014-09-21
• [Presentation] 遺伝性DNA修復異常疾患：家族性乳がんとファンコニ貧血 (2014)
  • Author(s): 高田 穣
  • Organizer: 日本家族性腫瘍学会 第１７回家族性腫瘍セミナー
  • Place of Presentation: 近畿大学・東大阪キャンパス
  • Year and Date: 2014-08-24
  • Invited
• [Presentation] ファンコニ貧血症とDNA修復メカニズム (2014)
  • Author(s): 髙田 穣
  • Organizer: 第３６回日本光医学・光生物学会シンポジウム
  • Place of Presentation: 大阪大学銀杏会館
  • Year and Date: 2014-07-25
  • Invited
• [Book] The Fanconi Anemia Pathway and Interstrand Cross-Link Repair in 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] 研究成果アーカイブ
  • URL: http://house.rbc.kyoto-u.ac.jp/research
• [Remarks] Radiation Biology Center, Kyoto University
  • URL: http://www.rbc.kyoto-u.ac.jp