Comprehensive Insights into DNA Recombinational Repair in the Human Genome

• Project/Area Number: 19H01151
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Medium-sized Section 63:Environmental analyses and evaluation and related fields
• Research Institution: Yokohama City University
• Principal Investigator: Adachi Noritaka 横浜市立大学, 生命ナノシステム科学研究科(八景キャンパス), 教授 (30264675)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥37,830,000 (Direct Cost: ¥29,100,000、Indirect Cost: ¥8,730,000); Fiscal Year 2022: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2021: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000); Fiscal Year 2020: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000); Fiscal Year 2019: ¥16,120,000 (Direct Cost: ¥12,400,000、Indirect Cost: ¥3,720,000)
• Keywords: 組換え修復 / DNA切断 / 生体環境 / ゲノム編集 / ゲノム編集細胞 / 組換え修復

Outline of Research at the Start

二本鎖DNAの切断は、細胞や個体にとって最も脅威となるゲノム損傷である。したがって、DNA切断の修復は化学物質の影響評価において優先的に考慮すべき生命現象の一つである。本研究では、二本鎖DNA切断修復システムの全体像をヒトゲノム編集細胞を駆使して明らかにするとともに、生体環境（特にヒ素などの重金属やその他の環境ホルモン様化学物質）の影響を系統的に解析し、その包括的な理解を目指す。本研究の成果は、環境化学物質のリスク評価、放射線や抗がん剤によるがん治療戦略など、幅広い分野への波及効果が期待できる。

Outline of Final Research Achievements

DNA double-strand breaks (DSBs) are the most threatening genomic damage to cells and individuals and must be repaired promptly. In this study, we aimed to elucidate the entire DSB repair system, especially the molecular mechanisms and physiological significance of two minor repair pathways, alt-EJ (aka TMEJ) and SSA, by utilizing human gene-knockout cell lines, which led us to obtain many novel findings. We also analyzed the effects of specific environmental chemicals by using a system that can quantitatively evaluate the individual activities of DNA recombinational repair, leading to several interesting findings.

Academic Significance and Societal Importance of the Research Achievements

二本鎖DNAの切断は、細胞や個体にとって最も脅威となるゲノム損傷である。したがって、DNA切断の発生機構とその修復機構の解明は極めて重要であり、化学物質の影響評価においても優先的に考慮されるべき生命現象の一つである。本研究では、二本鎖DNA切断修復システムの全体像をヒトゲノム編集細胞を駆使して明らかにするとともに、生体環境の影響についても解析することでその包括的な理解を目指した。本研究の成果は、DNA修復機構の基本的理解や環境化学物質の評価にとどまらず、放射線や抗がん剤によるがん治療戦略など、幅広い分野への波及効果も期待できる。

Research Products

• [Int'l Joint Research] UNIST(韓国)
• [Int'l Joint Research] USC/UCI(米国)
• [Int'l Joint Research] UNIST(韓国)
• [Int'l Joint Research] USC/UCI(米国)
• [Int'l Joint Research] UNIST(韓国)
• [Int'l Joint Research] USC/UCI(米国)
• [Int'l Joint Research] UNIST(韓国)
• [Int'l Joint Research] USC/UCI(米国)
• [Journal Article] A Cell System-Assisted Strategy for Evaluating the Natural Antioxidant-Induced Double-Stranded DNA Break (DSB) Style (2023)
  • Author(s): Yuduki Someya 1 , Sakine Kobayashi, Kazuya Toriumi, Shigeki Takeda, Noritaka Adachi, Aya Kurosawa
  • Journal Title: Genes (Basel) Volume: 14 Issue: 2 Pages: 420-420
  • DOI: 10.3390/genes14020420
  • Peer Reviewed / Open Access
• [Journal Article] Error-prone bypass patch by a low-fidelity variant of DNA polymerase zeta in human cells (2021)
  • Author(s): Suzuki Tetsuya、Sassa Akira、Gruz Petr、Gupta Ramesh C.、Johnson Francis、Adachi Noritaka、Nohmi Takehiko
  • Journal Title: DNA Repair Volume: 100 Pages: 103052-103052
  • DOI: 10.1016/j.dnarep.2021.103052
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Complex genetic interactions between DNA polymerase β and the NHEJ ligase. (2019)
  • Author(s): Kurosawa A, Kuboshima H, Adachi N.
  • Journal Title: FEBS J. Volume: 287 Issue: 2 Pages: 377-385
  • DOI: 10.1111/febs.15012
  • Peer Reviewed
• [Presentation] Functional analysis of human WHSC1 in DNA double-strand break repair (2020)
  • Author(s): 足立典隆、他
  • Organizer: 日本環境変異原学会第49回大会
• [Presentation] DNA polymerase theta is essential for alternative end-joining (2020)
  • Author(s): 足立典隆、他
  • Organizer: 第43回日本分子生物学会年会
  • Invited
• [Presentation] Introduction & Defining the mutation signatures of DNA polymerase θ in cancers (2020)
  • Author(s): 足立典隆
  • Organizer: 第43回日本分子生物学会年会
  • Invited