Molecular mechanism of large genome deletion induced byDisrupting BRCA1-related gene, FA-J.

• Project/Area Number: 19790234
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Pathological medical chemistry
• Research Institution: Kyushu University (2008); Kyoto University (2007)
• Principal Investigator: KITAO Hiroyuki Kyushu University, 医学研究院, 寄附講座教員 (30368617)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥3,780,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥480,000); Fiscal Year 2008: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2007: ¥1,700,000 (Direct Cost: ¥1,700,000)
• Keywords: ファンコニ貧血 / FANCJ / ゲノム不安定性 / 家族性乳癌 / BRCA1 / 家族性乳がん / BRCAI

Research Abstract

ファンコニ貧血(Fanconi Anemia, FA)はまれな小児遺伝性疾患で、骨髄不全、骨格異常、高発がん性が主な臨床症状である。平成17年、新たなFA原因遺伝子として同定されたFA-Jは、以前に家族性乳がん原因遺伝子BRCA1と会合するDNAヘリケースとして同定されたBACH1と同一であることが判明し、家族性乳がん発症とFA経路との関連が示唆された。申請者は、ニワトリDT40細胞FA-J破壊株を解析していたところ、免疫グロブリン重鎖(Immunoglobulin Heavy chain ; IgH)遺伝子座可変領域のVDJ組換えを完了した転写活性アリルが特異的に高頻度で染色体上から欠失を起こすことを見出し、平成19年度より本助成金を受け研究を開始した。平成19年度は、まずFA-J破壊株で見られるIgH遺伝子座欠失がIgH遺伝子座領域とその周辺に限局したものであることをFISH法などで明らかにした。平成20年に入り、FA-JにDNA上のG quadruplexという2次構造を解消する活性があることが報告された。IgH遺伝子座はG quadruplexを作りやすい配列を多く含んでおり、FA-J欠損のためうまく解消されずに残ったゲノム上の2次構造により上記表現型が現れると予想された。実際、FA-J欠損細胞は、G quadruplexを安定化する化合物TMPyP4に対して感受性を示した。FA-JとG quadruplexとの関連があることを支持する結果と考えられる。

Research Products

• [Journal Article] ファンコニ貧血とDNA損傷応答ネットワーク (2009)
  • Author(s): 松下暢子、北尾洋之、石合正道、高田穣
  • Journal Title: 蛋白質核酸酵素 54 Pages: 580-585
  • Peer Reviewed
• [Journal Article] ファンコニ貧血とゲノム不安定性 (2009)
  • Author(s): 北尾洋之、藤中良彦、久保信英、中ノ子智徳、吉永敬士、徳永えり子、佐伯浩司、遠藤和也、森田勝、掛地吉弘、前原喜彦
  • Journal Title: 福岡医学雑誌 99 Pages: 115-122
  • NAID: 120000981513
  • Peer Reviewed
• [Journal Article] FANCI phosphorylation functions as a molecular switch to turn on the Fanconi anemia pathway (2008)
  • Author(s): Ishiai M, Kitao H, Smogorzewska A, Tomida J, Kinomura A, Uchida E, SaberiA, Kinoshita E, Kinoshita-Kikuta E, Koike T, Tashiro S, Elledge SJ, Takata M
  • Journal Title: Nature Structural and Molecular Biology 15 Pages: 1138-1146
  • Peer Reviewed
• [Journal Article] ファンコニ貧血とゲノム不安定 (2008)
  • Author(s): 北尾洋之、藤中良彦、久保信英、中ノ子智徳、吉永士、徳永えり子、佐伯浩司、遠藤和也、森田勝、掛地吉弘、前原喜彦
  • Journal Title: 福岡医学雑誌 99 Pages: 115-122
  • Peer Reviewed
• [Journal Article] Regulation of histone H4 acetylation by transcription factor E2A in Ig gene conversion (2008)
  • Author(s): Kitao H, Kimura M, Yamamoto K, Seo H, Namikoshi K, Agata Y, Ohta K, Takata M
  • Journal Title: International Immunology 20 Pages: 277-284
• [Journal Article] Activation of downstream epidermal growth factor receptor (EGFR) signaling provides gefitinib-resistance in cells carrying EGFR muation (2008)
  • Author(s): Uchida A, Hirano S, Kitao H, Ogino A, Rai K, Toyooka S, Takigawa N, Tabata M, Takata M, Kiura K, Tanimoto M
  • Journal Title: Cancer Science 98 Pages: 357-363
  • Peer Reviewed
• [Journal Article] FANCI phosphorylation functions as a molecular switch to turn on the Fanconi anemia pathway (2008)
  • Author(s): Ishiai M, Kitao H, Smogorzewska A, Tomida J, Kinomura A, Uchida E, Saberi A, Kinoshita E, Kinoshita Kikuta E, Koike T, Tashiro S, Elledge SJ, Takata M
  • Journal Title: Nature Structural and Molecular Biology 15 Pages: 1138-1146
  • Peer Reviewed
• [Journal Article] Regulation of histone H4 acetylation by transcription factor E2A in immunoglobulin gene conversion. (2008)
  • Author(s): Kitao, H., Kimura, M., Yamamoto, K., Seo, H., Namikoshi, K., Agata, Y., Ohta, K., and Takata, M.
  • Journal Title: International Immunology 20 Pages: 277-284
  • Peer Reviewed
• [Journal Article] A requirement of FancL and FancD2 monoubiquitination in DNA repair (2007)
  • Author(s): Seki S, Ohzeki M, Uchida A, Hirano S, Matsushita N, Kitao H, Oda T, Yamashita T, Kashihara N, Tsubahara A, Takata M, Ishiai M
  • Journal Title: Genes to Cells 12 Pages: 299-310
  • Peer Reviewed
• [Journal Article] Emergence of epidermal growth factor receptor T790M mutation during chronic exposure to gefitinib in a non small cell lung cancer cell line (2007)
  • Author(s): Ogino A, Kitao H, Hirano S, Uchida A, Ishiai M, Kozuki T, Takigawa N, Takata M, Kiura K, Tanimoto M.
  • Journal Title: Cancer Research 67 Pages: 7807-7814
  • Peer Reviewed
• [Journal Article] Fanconi Anemia : genetic analysis of a human disease using chicken system (2007)
  • Author(s): Takata M, Kitao H, Ishiai M
  • Journal Title: Cytogenetic and Genome Research 117 Pages: 346-351
  • Peer Reviewed
• [Journal Article] ファンコニ貧血の分子機構 (2007)
  • Author(s): 北尾洋之、高田穣
  • Journal Title: 最新医学 62 Pages: 112-117
  • NAID: 40015288565
  • Peer Reviewed
• [Journal Article] Emergence of epidermal growth factor receptor T790M mutation during chronicexposure to gefitinib in a non small cell lung cancer cell line. (2007)
  • Author(s): Ogino, A., Kitao, H., Hirano, S., Uchida, A., Ishiai, M., Kozuki, T., Takigawa, N., Takata, M., Kiura, K., and Tanimoto, M.
  • Journal Title: Cancer Research 67 Pages: 7807-7814
  • Peer Reviewed
• [Presentation] Genomic instability phenotypes induced by loss of FancJ/Brip1 function (2009)
  • Author(s): Kitao H, Nanda I, Kakeji Y, Maehara Y, Takata M
  • Organizer: American Association for Cancer Research 100th Annual Meeting
  • Place of Presentation: Colorado Convention Center, Denver,CO
  • Year and Date: 2009-04-19
• [Presentation] ユビキチン化とリン酸化によるファンコニ貧血経路の制御機構 (2008)
  • Author(s): 石合正道、北尾洋之、高田穣
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2008-10-29
• [Presentation] FancJ/Brip1ヘリカーゼ欠損により生じるゲノム不安定性表現型 (2008)
  • Author(s): 北尾洋之、Indrajit Nanda、木野村愛子、山添光芳、Michael Schmid、武田俊一、吉永敬士、前原喜彦、高田穣
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2008-10-28
• [Presentation] BRCmotif-RPA融合蛋白はBRCA2欠損細胞の相同組換え修復異常を相補する (2008)
  • Author(s): 佐伯浩司、北尾洋之、江見泰徳、森田勝、掛地吉弘、前原喜彦、Maria Jasin
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2008-10-28
• [Presentation] FancJ/Brip1ヘリカーゼ欠損により生じるゲノム不安定性症候群 (2008)
  • Author(s): 北尾洋之
  • Organizer: 日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2008-10-28
• [Presentation] Takata M. Frequent loss of the Immunoglobulin heavy chain gene occurs in FANCJ-deficient DT40 cell line (2008)
  • Author(s): Kitao H, Nanda I, Kinomura A, Schmid M, Takata M
  • Organizer: Ataxia-Telangiectasia Workshop 2008
  • Place of Presentation: 大津プリンスホテル
  • Year and Date: 2008-04-25
• [Presentation] Frequent loss of the Immunoglobulin Heavy Chain Gene Occurs in FANCJ-deficient DT40 cell line (2007)
  • Author(s): Kitao H, Nanda I, Kinomura A, Schmid M, Takata M
  • Organizer: 19th Annual Fanconi Anemia Research Fund Scientific Symposium
  • Place of Presentation: The Westin Michigan Avenue, Chicago, IL.
  • Year and Date: 2007-10-10
• [Presentation] Role of FANCI protein and its pathway function (2007)
  • Author(s): Takata M, Kitao H, Kinomura A, Smogorzewska A, Elledge SJ, Ishiai M
  • Organizer: 19th Annual Fanconi Anemia Research
  • Place of Presentation: The Westin Michigan Avenue, Chicago, IL.
  • Year and Date: 2007-10-10
• [Presentation] Frequent loss of the immunoglobulin heavy chain geneoccurs in FANCJ-deficient DT40 cells (2007)
  • Author(s): Hiroyuki Kitao
  • Organizer: 19th Annual Fanconi Anemia Research Fund Scientific Symposium
  • Place of Presentation: Chicago, MI
  • Year and Date: 2007-10-10
• [Presentation] FancJ/BRIP1 helicasedeficient cells display huge loss of rearranged IgH locus (2007)
  • Author(s): Kitao H, Kinomura A, Kimura M, Ishiai M, Takata M
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2007-10-05
• [Presentation] Emergence of EGFR T790M mutation during chronic exposure to gefitinib in a non-small cell lung cancer cell line (2007)
  • Author(s): Ogino A, Kitao H, Uchida A, Ishiai M, Takigawa N, Takata M, Kiura K, Tanimoto M
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2007-10-05
• [Presentation] Regulation of DNA crosslink repair through monoubiquitination mediated by the Fanconi anemia core complex (2007)
  • Author(s): Takata M, Kitao H, Kinomura A, Ishiai M
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2007-10-03
• [Remarks]
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• [Remarks]
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