BRCA1ユビキチンリガーゼによるDNA損傷応答

• Project Area: Proteolysis in the Regulation of Biological Processes
• Project/Area Number: 21025032
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: St. Marianna University School of Medicine
• Principal Investigator: 太田 智彦 聖マリアンナ医科大学, 医学(系)研究科(研究院), 教授 (60233136)
• Project Period (FY): 2009 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥6,400,000 (Direct Cost: ¥6,400,000); Fiscal Year 2010: ¥3,200,000 (Direct Cost: ¥3,200,000); Fiscal Year 2009: ¥3,200,000 (Direct Cost: ¥3,200,000)
• Keywords: BRCA1 / ubiquitin / DNA損傷 / NPM1 / DUB

Research Abstract

本研究では乳癌の化学療法感受性を左右するBRCA1のE3活性の役割を解析した。平成22年度はNPM1、BAP1、I26A変異について21年度の結果に加え、以下の結果を得た。
1.NPM1 : Thr199がリン酸化したNPM1のDNA二本鎖切断への集積はRNF168が必須であった。siRNAにより内因性NPM1を抑制し野生型NPM1あるいは非リン酸化型変異であるT199A-NPM1をadd-backした細胞を用いてDNA損傷応答を解析した結果、T199A-NPM1ではDNA損傷修復が著明に欠落していることがneutral comet assayにて証明された。BRCA1が欠失しているUWB1.289細胞および同細胞にBRCA1を安定発現している細胞を用いて、電離放射線を照射したところ、BRCA1依存的に内因性のNPM1のポリユビキチン化が生じた。平成21年度の結果とあわせ、NPM1はDNAの相同組換え修復経路で必須の役割を果たすBRCA1の基質であると考えられた。
2.BAP1 : BAP1の変異体がメラノーマの原因となることが報告されたため、この変異体のBARD1との結合能を解析したところ、BARD1との結合が阻害された。
3.BRCA1のE3活性と薬剤感受性:BRCA1死活型変異I26Aをもちいた実験にてBRCA1 E3活性の欠損はDNA架橋剤に対する感受性には影響しないが、PARP阻害剤とイリノテカン(CPT-11)に対する感受性を著明に亢進させることがわかった。

Research Products

• [Journal Article] A mitotic role for the DNA damage-responsive CHK2 kinase. (2010)
  • Author(s): Sato K
  • Journal Title: Nature Cell Biology Volume: 12 Pages: 424-5
  • Peer Reviewed
• [Journal Article] HERC2 is an E3 ligase that targets BRCA1 for degradation. (2010)
  • Author(s): Wu W
  • Journal Title: Cancer Research Volume: 70 Pages: 6384-92
  • Peer Reviewed
• [Journal Article] Recruitment of phosphorylated NPM1 to sites of DNA damage through RNF8-dependent ubiquitin conjugates. (2010)
  • Author(s): Koike A
  • Journal Title: Cancer Research Volume: 70 Pages: 6746-56
  • Peer Reviewed
• [Journal Article] Hoxb4 transduction down-regulates Geminin protein, providing hematopoietic stem and progenitor cells with proliferation potential. (2010)
  • Author(s): Ohno Y
  • Journal Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 107 Pages: 21529-34
  • Peer Reviewed
• [Journal Article] Prediction of breast cancer sensitivity to neoadjuvant chemotherapy based on status of DNA damage repair proteins. (2010)
  • Author(s): Asakawa H
  • Journal Title: Breast Cancer Research Volume: 12
  • Peer Reviewed
• [Journal Article] BRCA遺伝子異常と標的治療 (2010)
  • Author(s): 太田智彦
  • Journal Title: がん分子標的治療 Volume: 8 Pages: 46-52
  • Peer Reviewed
• [Journal Article] DNA損傷応答と乳癌の薬剤感受性 (2010)
  • Author(s): 太田智彦
  • Journal Title: 乳癌の臨床 Volume: 25 Pages: 609-15
  • Peer Reviewed
• [Journal Article] 乳がん (2010)
  • Author(s): 太田智彦
  • Journal Title: 日本臨林 遺伝子診療学(第2版) Volume: 984 Pages: 438-43
  • Peer Reviewed
• [Journal Article] Amitotic role fbr the DNA damage-responsive CHK2 Kinase (2010)
  • Author(s): Ko Sato, et al
  • Journal Title: Nature Cell Biology 12(In press)
• [Journal Article] Prediction of breast cancer sensitivity to neoadjuvant chemotherapy ba sed on status of DNA damage repair proteins (2010)
  • Author(s): Hideki Asakawa, et al
  • Journal Title: Breast Cancer Res. 12
  • Peer Reviewed
• [Journal Article] Clinicopathological analyses of triple negative breast cancer using surveillance data from the Registration Committee of the Japanese Breast Cancer Society. (2010)
  • Author(s): Hirotaka Iwase, et al
  • Journal Title: Breast Cancer 17 Pages: 118-24
  • Peer Reviewed
• [Journal Article] がんのゲノム解析と診療への応用a)乳がん (2010)
  • Author(s): 太田智彦
  • Journal Title: 日本臨牀 (In press)
• [Journal Article] BRCA遺伝子異常と標的治療 (2010)
  • Author(s): 太田智彦
  • Journal Title: がん分子標的治療 (In press)
• [Journal Article] Radiologic-pathological correlation of punctate hyperechoic foci by ultrasound in stereotactic vacuum-assisted breast biopsy samples. (2009)
  • Author(s): Hiroko Okazakl, et al
  • Journal Title: Jpn J Radiol. 27 Pages: 438-43
  • Peer Reviewed
• [Journal Article] Contemplating chemosensitivity of basal-like breast cancer based on BRCA1 dysfunction. (2009)
  • Author(s): Tomohiko Ohta
  • Journal Title: Breast Cancer 16 Pages: 268-74
  • NAID: 10027254733
  • Peer Reviewed
• [Journal Article] Perturbation of DNA repair pathways by proteasome inhibitors corres ponds to enhanced chemosensitivity of cells to DNA damage-inducing agents. (2009)
  • Author(s): Takashi Takeshita, et al
  • Journal Title: Cancer Chemother Pharmacol. 64 Pages: 1039-46
  • Peer Reviewed
• [Presentation] The DNA damage repair pathway in breast cancer chemotherapy (2010)
  • Author(s): Tomohiko Ohta
  • Organizer: The 23rd International Symposium of the Foundation for Promotion of Cancer Research "Recent Progress on Breast
  • Place of Presentation: 東京(国立がんセンター)
• [Presentation] DNA損傷応答と乳癌の薬剤感受性 (2010)
  • Author(s): 太田智彦
  • Organizer: 第18回日本乳癌学会学術総会、シンポジウム
  • Place of Presentation: 北海道(ロイトン札幌)
• [Presentation] Recruitment of phosphorylated NPM1 to sites of DNA damage through RNF8-dependent ubiquitin conjugates. (2010)
  • Author(s): Tomohiko Ohta
  • Organizer: EMBO Workshop-The interface between the ubiquitin family and the DNA damage response.-
  • Place of Presentation: Croatia (Hotel Istra)
• [Presentation] 乳がんのDNA相同組換え修復異常とユビキチン (2010)
  • Author(s): 太田智彦
  • Organizer: 第69回日本癌学会学術総会、シンポジウム
  • Place of Presentation: 大阪(大阪国際会議場)
• [Presentation] 乳癌の化学療法感受性とBRCA1 (2009)
  • Author(s): 太田智彦
  • Organizer: 第19回乳癌基礎研究会
  • Place of Presentation: 伊香保温泉(群馬県)
  • Year and Date: 2009-07-25
• [Presentation] REGULATION OF NUCLEOPHOSMIN BY BRCAI E3 UBIQ UITIN LIGASE (2009)
  • Author(s): Ayaka Koike, et al
  • Organizer: Cold Spring Harbor Laboratory Meeting -The Ubiquitin Family-
  • Place of Presentation: New York, USA
  • Year and Date: 2009-04-22
• [Presentation] The E3 ligase activity of HERC2 regulates BRCA1-mediated G2/M checkpoint function independent of BARD1 (2009)
  • Author(s): Wenwen Wu, et al
  • Organizer: Cold Spring Harbor Laboratory Meeting-The Ubiquitin Family-
  • Place of Presentation: New York, USA
  • Year and Date: 2009-04-22
• [Presentation] BRCA1機能不全をtargetにした乳癌の化学療法 (2009)
  • Author(s): 太田智彦
  • Organizer: 第109回日本外科学会定期学術集会
  • Place of Presentation: 福岡国際会議場(福岡県)
  • Year and Date: 2009-04-02
• [Remarks]
  • URL: http://www.marianna-u.ac.jp/t-oncology/index.html
• [Remarks]
  • URL: http://www.marianna-u.ac.jp/t-oncology/