English title

• Project/Area Number: 17K00548
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Risk sciences of radiation and chemicals
• Research Institution: Kyoto University
• Principal Investigator: Motegi Akira 京都大学, 医学研究科, 助教 (80452332)
• Project Period (FY): 2017-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: DNA損傷トレランス / 複製後修復 / 相同組換え / ユビキチン

Outline of Final Research Achievements

In this study, I have addressed to the possible functional relationships between the replication fork reversal (RFR) pathway and the homology-dependent repair (HDR) pathway in vertebrate cells by generating and analyzing DT40 cell lines doubly deficient in one of the RFR genes 1)SHPRH, 2) RAD18, or 3)ZRANB3 along with the HDR gene BRCA1. I observed the enhanced sensitivity towards the PARP inhibitor Olaparib, defects in the gene targeting efficiencies, and reduced rates of the recombination in the substrate assay in double knock-out (KO) cells than BRCA1 single KO cells. All of those results suggests that RFR may have competitive roles with HDR in promoting the restoration of stalled replication forks.

Academic Significance and Societal Importance of the Research Achievements

複製ブロックの解除は生命にとって根源的な課題である遺伝情報の複製・維持において必須の仕組みである。本研究の対象であるRFR経路は、複製ブロックの解除において従来からよく知られている相同組換えと論理的に競合しうるが、それを逆遺伝的手法によって検証、実証した点に学術的意義がある。また、新しいタイプの抗がん剤として注目されているPARP阻害剤はBRCA1の機能を欠損したがんでより致死作用が強いが、その作用機序として複製再開の仕組みとの関連が考えられる。本研究の結果はPARP阻害剤をはじめとした新しいがん治療薬の作用機序についての基礎的知見を提供する点に社会的意義がある。

Research Products

• [Journal Article] HDAC3 is required for XPC recruitment and nucleotide excision repair of DNA damage induced by UV irradiation (2020)
  • Author(s): 1.Koji Nishimoto, Hiroyuki Niida, Chiharu Uchida, Tatsuya Ohhata, Kyoko Kitagawa, Akira Motegi, Takafumi Suda, and Masatoshi Kitagawa
  • Journal Title: Mol. Cancer Res. Volume: 18 Issue: 9 Pages: 1367-1378
  • DOI: 10.1158/1541-7786.mcr-20-0214
  • NAID: 120007165672
  • Peer Reviewed
• [Journal Article] Aberrations in DNA repair pathways in cancer and therapeutic significances (2019)
  • Author(s): Akira Motegi, Mitsuko Masutani, Ken-ichi Yoshioka, and Tadashi Bessho
  • Journal Title: Seminars in Cancer Biology Volume: 58 Pages: 29-46
  • DOI: 10.1016/j.semcancer.2019.02.005
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] PARI regulates stalled replication fork proessing to maintain genome stability upon replication stress in mice (2017)
  • Author(s): Ayako L. Mochizuki, Ami Katanaya, Eri Hayashi, Mihoko Hosokawa, Emiko Moribe, Akira Motegi, Masamichi Ishiai,Minoru Takata, Gen Kondoh, Hitomi Watanabe, Norio Nakatsuji, and Shinichiro Chuma
  • Journal Title: Mol. Cell. Biol Volume: 37 (23) Issue: 23
  • DOI: 10.1128/mcb.00117-17
  • Peer Reviewed / Open Access
• [Journal Article] Phosphorylated HBO1 at UV irradiated sites is essential for nucleotide excision repair (2017)
  • Author(s): Niida, H., Matsunuma, R., Horiguchi, R., Uchida, C., Nakazawa, Y., Motegi, A., Nishimoto, K., Sakai, S., Ohhata, T., Kitagawa, K., Moriwaki, S., Nishitani, H., Ui, A., Ogi, T. and Kitagawa, M.
  • Journal Title: Nature Communications Volume: 8 Issue: 1 Pages: 16102-16102
  • DOI: 10.1038/ncomms16102
  • Peer Reviewed / Open Access
• [Presentation] HDAC3 induces translocation of XPC from active gene promoters to DNA lesions alter UV irradiation to promote nucleotide excision repair (2019)
  • Author(s): Hiroyuki Niida, Koji Nishimoto, Akira Motegi, Masatochi Kitagawa
  • Organizer: 第62回日本影響学会大会
• [Presentation] ユビキチンリガーゼによるDNA損傷トレランスの制御機構 (2019)
  • Author(s): Akira Motegi
  • Organizer: 日本核酸医薬学会 生物セッション第4回サテライトシンポジウム2019
  • Invited
• [Presentation] PARI regulates stalled replication fork proessing to maintain genome stability upon replication stress in mice (2017)
  • Author(s): Ayako L. Mochizuki, Ami Katanaya, Eri Hayashi, Mihoko Hosokawa, Emiko Moribe, Akira Motegi, Masamichi Ishiai,Minoru Takata, Gen Kondoh, Hitomi Watanabe, Norio Nakatsuji, and Shinichiro Chuma
  • Organizer: 第89回日本遺伝学会大会