Molecular mechanisms of crosstalk between DNA-damage response and signal transduction

• Project/Area Number: 25290044
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Hamamatsu University School of Medicine
• Principal Investigator: Kitagawa Masatoshi 浜松医科大学, 医学部, 教授 (50294971)
• Co-Investigator(Kenkyū-buntansha): 松本 雅記 九州大学, 生体防御医学研究所, 准教授 (60380531)
• Co-Investigator(Renkei-kenkyūsha): NIIDA Hiroyuki 浜松医科大学, 医学部, 准教授 (20336671)
• Project Period (FY): 2013-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥17,030,000 (Direct Cost: ¥13,100,000、Indirect Cost: ¥3,930,000); Fiscal Year 2015: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2014: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2013: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
• Keywords: DNA障害応答 / シグナル伝達 / リン酸化 / DNA損傷応答

Outline of Final Research Achievements

We found that Mig-6, an internal inhibitor of EGFR,is phosphorylated accompanied by EGF stimulation but also UV-irradiation. The results suggest that there is a crosstalk between EGF-signaling and DNA-damage response. Next, we found that HBO1,a histone acetyltransferase, phosphorylated Ser50/Ser53 of HBO1 by ATR after UV irradiation. HBO1 is ubiquitylated by CUL4-DDB1/DDB2 and degraded 6h after UV-irradiation. Moreover, we found that HBO1 participated in nucleotide excision repair(NAR). UV-DNA-damege induced phosphorylation of HBO1 promoted acetylation of histone H3 to induce structural change of chromatin in the damaged sites. These results suggested that the HBO1-mediated chromatin conformational change promoted recruitment of NER-related factors to enhanced the NER.

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] Interaction between RB protein and NuMA is required for proper alignment of spindle microtubules (2014)
  • Author(s): Uchida, C., Hattori, T., Takahashi, H., Yamamoto, N., Kitagawa, M. and Taya, Y.
  • Journal Title: Genes Cells Volume: 19 Issue: 2 Pages: 89-96
  • DOI: 10.1111/gtc.12119
  • 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] 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] Roles of the Skp2/p27 axis in the progression of chronic nephropathy (2012)
  • Author(s): Suzuki, S., Ohashi, N. and Kitagawa, M
  • Journal Title: Cell Mol Life Sci Volume: (in press) Issue: 18 Pages: 3277-3289
  • DOI: 10.1007/s00018-012-1232-x
  • Peer Reviewed
• [Presentation] A nobel substrate for Fbw7, the tumor suppressive ubiquitin ligase (2013)
  • Author(s): Masatoshi Kitagawa, Kyoko Kitagawa
  • Organizer: 第72回日本癌学会総会
  • Place of Presentation: 横浜
• [Presentation] ATM/ATR-dependent phosphorylation dissociates HBO1 from replication origin (2013)
  • Author(s): 丹伊田浩行、塩谷文章、松本雅記、西谷秀男、北川雅敏
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸
• [Remarks] 国立大学法人浜松医科大学医学部分子生物学講座
  • URL: https://www.hama-med.ac.jp/uni_education_igakubu_igaku_seika1.html
• [Remarks] 浜松医科大学・医学部・分子生物学講座
  • URL: https://www.hama-med.ac.jp/uni_education_igakubu_igaku_seika1.html
• [Remarks] 浜松医科大学医学部 分子生物学講座
  • URL: http://www.hama-med.ac.jp/uni_education_igakubu_igaku_seika1.html