How trans-lesion synthesis promote tumorigenesis?

• Project/Area Number: 18K11646
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 63020:Radiation influence-related
• Research Institution: Kumamoto University
• Principal Investigator: Tateishi Satoshi 熊本大学, 発生医学研究所, 講師 (00227109)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 損傷トレランス / RAD18 / ヒストン / ヒストンメチル化酵素 / ユビキチン / 放射線 / 発癌 / エピジェネティクス / Rad18 / 細胞老化 / UV / 損傷乗越え複製 / ヒストンメチル化修飾 / CRL4Cdt2 / DNAの再複製

Outline of Final Research Achievements

We found that purified human RAD18 / RAD6B complex protein have an activity of mono- and polyubiquitinating histone H2A protein. Irradiation of cells with ionizing radiation increased the ubiquitination level of chromatin protein. The level was reduced in RAD18-deficient cells. RAD18 is thought to ubiquitinate chromatin proteins in response to ionizing radiation. The expression level of histone methyltransferase was decreased in RAD18-deficient cells. It was suggested that RAD18 regulates the expression level of histone methyltransferase. RAD18 is thought to regulate the expression of various genes through histone methylation regulation.

Academic Significance and Societal Importance of the Research Achievements

E3酵素であるRAD18は、DNA複製部位へ集積し損傷乗越え複製を複製停止部位に集積させることで、 損傷乗越え複製を促進する機能をもつ。Rad18欠損マウスは、損傷乗越え複製酵素η欠損マウスと異なる表現型が見られた。RAD18には、損傷乗越え複製の制御とは異なる機序でゲノムを安定化する機構があると推論した。今回の研究で、RAD18は新たにヒストンタンパクのユビキチン化とメチル化に関与していることが示された。RAD18は正常細胞の増殖を維持する一方で、癌化した細胞の増殖も助けてしまう面をもつ。今回の研究成果が、老化の抑制研究または新規の抗癌剤の開発につながることが期待される。

Research Products

• [Int'l Joint Research] ノースカロライナ大学(米国)
• [Int'l Joint Research] ミネソタ大学(米国)
• [Int'l Joint Research] ノースカロライナ大学チャペルヒル校(米国)
• [Int'l Joint Research] ノースカロライナ大学チャペルヒル校/病理学部/Cyrus Vaziri 博士(米国)
• [Journal Article] RAD18 mediates DNA double-strand break-induced ubiquitination of chromatin protein (2021)
  • Author(s): Mustofa Md Kawsar、Tanoue Yuki、Chirifu Mami、Shimasaki Tatsuya、Tateishi Chie、Nakamura Teruya、Tateishi Satoshi
  • Journal Title: The Journal of Biochemistry Volume: in press Issue: 1 Pages: 33-40
  • DOI: 10.1093/jb/mvab010
  • NAID: 40022722273
  • Peer Reviewed
• [Journal Article] Rad18 mediates specific mutational signatures and shapes the genomic landscape of carcinogen-induced tumors in vivo. (2021)
  • Author(s): Lou J, Yang Y, Gu Q, Price BA, Qiu Y, Fedoriw Y, Desai S, Mose LE, Chen B, Tateishi S, Parker JS, Vaziri C, Wu D.
  • Journal Title: NAR Cancer Volume: 3(1) Issue: 1
  • DOI: 10.1093/narcan/zcaa037
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] In Silico Drug Repurposing by Structural Alteration after Induced Fit: Discovery of a Candidate Agent for Recovery of Nucleotide Excision Repair in Xeroderma Pigmentosum Group D Mutant (R683W) (2021)
  • Author(s): Takaoka Yutaka、Ohta Mika、Tateishi Satoshi、Sugano Aki、Nakano Eiji、Miura Kenji、Suzuki Takashi、Nishigori Chikako
  • Journal Title: Biomedicines Volume: 9 Issue: 3 Pages: 249-249
  • DOI: 10.3390/biomedicines9030249
  • NAID: 120007026365
  • Peer Reviewed / Open Access
• [Journal Article] Roles of Chk2/CHEK2 in guarding against environmentally induced DNA damage and replication-stress. (2020)
  • Author(s): Mustofa MK, Tanoue Y, Tateishi C, Vaziri C, Tateishi S.
  • Journal Title: Environ Mol Mutagen. Volume: 61(7) Issue: 7 Pages: 730-735
  • DOI: 10.1002/em.22397
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Differential roles of Rad18 and Chk2 in genome maintenance and skin carcinogenesis following UV exposure. (2018)
  • Author(s): Tanoue, Y., Toyoda, T., Sun, J, Mustofa, M.K., Tateishi, C., Endo, S., Motoyama, N., Araki, K., Wu, D., Okuno, Y., Tsukamoto, T., Takeya, M., Ihn, H., Vaziri, C., Tateishi, S.
  • Journal Title: J. Invest. Dermatol. Volume: 138 Issue: 12 Pages: 2550-2557
  • DOI: 10.1016/j.jid.2018.05.015
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] DNA repair protein Rad18 restricts LINE-1 mobility (2018)
  • Author(s): Ariumi Yasuo、Kawano Koudai、Yasuda-Inoue Mariko、Kuroki Misao、Fukuda Hiroyuki、Siddiqui Rokeya、Turelli Priscilla、Tateishi Satoshi
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 15894-15894
  • DOI: 10.1038/s41598-018-34288-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Diverse roles of RAD18 and Y-family DNA polymerases in tumorigenesis. (2018)
  • Author(s): Yang, Y., Gao, Y., Zlatanou, A., Tateishi, S., Yurchenko, V., Rogozin, I.B., Vaziri, C.
  • Journal Title: Cell Cycle Volume: 17 Issue: 7 Pages: 833-843
  • DOI: 10.1080/15384101.2018.1456296
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] タンパク質のモノユビキチン化 (2018)
  • Author(s): 立石 智
  • Journal Title: 生体の科学 Volume: 69 Pages: 123-127
  • Peer Reviewed
• [Presentation] Possible role of Rad18 in preventing cellular senescence (2019)
  • Author(s): Kawsar Md Mustofa, Satoshi Tateishi
  • Organizer: 日本分子生物学会年会 第42回大会
• [Presentation] Differential roles of Rad18 and Chk2 in genome maintenance and skin carcinogenesis following UV exposure (2018)
  • Author(s): Kawsar Md Mustofa, Yuki Tanoue, Satoshi Tateishi
  • Organizer: 日本分子生物学会年会 第41回大会
• [Remarks] 熊本大学 発生医学研究所 損傷修復分野 ホームページ
  • URL: http://www.imeg.kumamoto-u.ac.jp/bunya_top/department_of_cell_maintenance/
• [Remarks] 熊本大学 発生医学研究所 損傷修復分野
  • URL: http://www.imeg.kumamoto-u.ac.jp/bunya_top/department_of_cell_maintenance/
• [Remarks] Kumamoto Univ. IMEG, Dept. Cell Maintenance
  • URL: http://www.imeg.kumamoto-u.ac.jp/en/bunya_top/department_of_cell_maintenance/
• [Remarks]
  • URL: http://www.imeg.kumamoto-u.ac.jp/bunya_top/department_of_cell_maintenance/