Analysis of novel mechanism for regulation of DNA replication start

• Project/Area Number: 24390072
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Hamamatsu University School of Medicine
• Principal Investigator: Niida Hiroyuki 浜松医科大学, 医学部, 准教授 (20336671)
• Project Period (FY): 2012-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2014: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2013: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2012: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000)
• Keywords: HBO1 / DDB2 / ユビキチン / UV / DNA複製 / ATM/ATR / DNA損傷応答 / チェックポイント / ライセンシング / DNAダメージ / DNA損傷修復

Outline of Final Research Achievements

HBO1 plays positive regulation for cell proliferation under unperturbed condition, whether there is regulation mechanism of HBO1 under DNA damage is poorly understood. We demonstrated that HBO1 was degraded after DNA damage to suppress cell proliferation. Ser50 and Ser53 of HBO1 were ATM and ATR-dependently phosphorylated after UV treatment. ATM/ATR-dependent phosphorylated HBO1 preferentially interacted with DDB2 and was ubiquitylated by CRL4DDB2. Replacement of endogenous HBO1 to Ser50/53Ala mutants maintained acetylation of histone H3K14 and impaired cell cycle regulation in response to UV. These results indicated that HBO1 is one of the targets by DNA damage checkpoint. These results show that ubiquitin-dependent control of HBO1 protein contributes to cell survival toward UV irradiation.

Research Products

• [Journal Article] UV Damage-Induced Phosphorylation of HBO1 Triggers CRL4DDB2-Mediated Degradation To Regulate Cell Proliferation. (2015)
  • Author(s): Matsunuma R, Niida H, Ohhata T, Kitagawa K, Sakai S, Uchida C, Shiotani B, Matsumoto M, Nakayama KI, Ogura H, Shiiya N, Kitagawa M.
  • Journal Title: Mol Cell Biol. Volume: 36 Issue: 3 Pages: 394-406
  • DOI: 10.1128/mcb.00809-15
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] YB1 binds to and represses the p16 tumor suppressor gene. (2013)
  • Author(s): Kotake Y, Ozawa Y, Harada M, Kitagawa K, Niida H, Morita Y, Tanaka K, Suda T, Kitagawa M.
  • Journal Title: Genes Cells. Volume: 11 Issue: 11 Pages: 999-1006
  • DOI: 10.1111/gtc.12093
  • Peer Reviewed
• [Journal Article] Cell cycle regulation by long non-coding RNAs. (2013)
  • Author(s): Kitagawa M, Kitagawa K, Kotake Y, Niida H, Ohhata T.
  • Journal Title: Cell Mol Life Sci. Volume: 24 Issue: 24 Pages: 4785-4794
  • DOI: 10.1007/s00018-013-1423-0
  • Peer Reviewed
• [Journal Article] Involvement of ribonucleotide reductase-M1 in 5-fluorouracil induced DNA damage in esophageal cancer cell lines. (2013)
  • Author(s): Aoki Y, Sakogawa K, Hihara J, Emi M, Hamai Y, Kono K, Shi L, Sun J, Kitao H, Ikura T, Niida H, Nakanishi M, Okada M, Tashiro S.
  • Journal Title: Int J Oncol. Volume: 42(6) Issue: 6 Pages: 1951-60
  • DOI: 10.3892/ijo.2013.1899
  • Peer Reviewed
• [Journal Article] Regulation of DNA replication licensing. (2012)
  • Author(s): 丹伊田浩行、北川雅敏
  • Journal Title: Curr Drug Targets. Volume: 13 Pages: 1588-1592
  • Peer Reviewed
• [Presentation] DDB2-dependent HBO1 recruitment is required for efficient repair of UV-induced cyclobutane pyrimidine dimmer (2015)
  • Author(s): Hiroyuki Niida
  • Organizer: IMB conference 2015
  • Place of Presentation: Mainz, ドイツ
  • Year and Date: 2015-06-04
  • Int'l Joint Research
• [Presentation] DDB2-dependent HBO1 recruitment is essential for repair of UV-induced cyclobutane pyrimidine dimmer (2014)
  • Author(s): 丹伊田浩行
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] DDB2-dependent HBO1 recruitment is required for efficient repair of UV-induced cyclobutane pyrimidine dimmer (2014)
  • Author(s): 丹伊田浩行
  • Organizer: 日本放射線影響学会 第57回大会
  • Place of Presentation: かごしま県民交流センター
  • Year and Date: 2014-10-01 – 2014-10-03
• [Presentation] DDB2依存的HBO1リクルートはUVにより生じるシクロブタン型ピリミジンダイマーの効果的な修復に必要である (2014)
  • Author(s): 丹伊田浩行
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Regulation of Licensing by Cell Cycle Checkpoint (2013)
  • Author(s): Hiroyuki Niida
  • Organizer: 第６５回日本細胞生物学会大会
  • Place of Presentation: ウインクあいち
  • Invited
• [Presentation] UV損傷における複製ライセンスファクターの制御 (2013)
  • Author(s): Hiroyuki Niida
  • Organizer: 日本放射線影響学会第５６回大会
  • Place of Presentation: ホテルクラウンパレス青森
  • Invited
• [Presentation] ATM/ATR-dependent phosphorylation dissociates HBO1 from replication origin (2013)
  • Author(s): Hiroyuki Niida
  • Organizer: 第３６回に本分子生物学会年会
  • Place of Presentation: 神戸国際会議場
• [Presentation] ATM/ATR-dependent phosphorylation of HBOl suppresses pre-RC formation after DNA damage (2012)
  • Author(s): 丹伊田浩行
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡マリンメツセ
  • Year and Date: 2012-12-12
• [Presentation] ATM/ATR-dependent phosphorylation of HBOl s required for HBO 1 dissociation from replication origin (2012)
  • Author(s): 丹伊田浩行
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌ロイトン
  • Year and Date: 2012-09-19