Molecular mechanisms of mutation induction and suppression by DNA polymerase zeta

• Project/Area Number: 17K12824
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Risk sciences of radiation and chemicals
• Research Institution: Hiroshima University
• Principal Investigator: Suzuki Tetuya 広島大学, 医系科学研究科(薬), 助教 (20573950)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 損傷乗り越えDNA合成 / DNAポリメラーゼζ / 変異 / DNA損傷 / 損傷乗り越え合成 / DNA修復 / 環境変異原 / 癌

Outline of Final Research Achievements

DNA polymeraseζ(polζ), which is one of translesion DNA polymerases, extends several nucleotides in an error-prone manner bypass through DNA lesions. In this study, the mechanisms of mutagenesis by polζin replication across benzopyrene diol epoxide-guanine adduct (BPDE-dG) were analyzed. BPDE-dG in the lagging strand template induced more mutations in cells expressing low-fidelity polζ than that in the leading strand template. Moreover, mismatch repair could not suppress mutations mediated by translesion DNA synthesis across BPDE-dG by polζ.

Academic Significance and Societal Importance of the Research Achievements

DNA polymeraseζが損傷乗り越えDNA合成時に誘発する変異に合成鎖が影響しうることを明らかにすることができた。また、ミスマッチ修復はそれらの変異を抑制しない可能性も示した。今後、さらにその他の因子との関連を研究することによりPolζによる変異誘発の分子機構の解明と発癌との関連を明らかにできることが期待される。また、本研究により開発したノックインによる標的遺伝子への変異導入法は効率的なモデル細胞/動物の作製への応用も期待される。

Research Products

• [Journal Article] Large deletions and untargeted substitutions induced by abasic site analog on leading versus lagging strand templates in human cells (2019)
  • Author(s): Suzuki Tetsuya、Katayama Yuri、Komatsu Yasuo、Kamiya Hiroyuki
  • Journal Title: Mutagenesis Volume: 34 Pages: 421-429
  • DOI: 10.1093/mutage/gez034
  • Peer Reviewed
• [Presentation] supF遺伝子変異解析のための新規大腸菌株の作製 (2020)
  • Author(s): 福島瑠璃子, 鈴木哲矢, 河合秀彦, 紙谷浩之
  • Organizer: 日本薬学会第140年会
• [Presentation] DNAポリメラーゼζが損傷乗り越え合成時に誘発する変異へのDNA合成鎖の影響 (2019)
  • Author(s): 坂倉直人, 鈴木哲矢, 紙谷浩之
  • Organizer: 第58回日本薬学会中国四国支部学術大会
• [Presentation] 核酸を基盤とした変異誘発の分子機構の解明および遺伝子治療法の開発 (2019)
  • Author(s): 鈴木哲矢
  • Organizer: 第58回日本薬学会中国四国支部学術大会
• [Presentation] OGG1-knockdown increases large deletions but decreases untargeted substitutions induced by 8-oxo-7,8-dihydroguanine (2019)
  • Author(s): Yudai Zaima, Tetsuya Suzuki, Hiroyuki Kamiya
  • Organizer: The Joint Meeting of The 6th Asian Congress on Environmental Mutagens(ACEM) and the 48th Annual Meeting of the Japanese Environmental Mutagen Society(JEMS)
  • Int'l Joint Research
• [Presentation] Abasic site analog in lagging strand template induces mutations more frequency than that in leading strand template (2019)
  • Author(s): Tetsuya Suzuki, Yuri Katayama, Hiroyuki Kamiya
  • Organizer: The Joint Meeting of The 6th Asian Congress on Environmental Mutagens(ACEM) and the 48th Annual Meeting of the Japanese Environmental Mutagen Society(JEMS)
  • Int'l Joint Research
• [Presentation] 転写鎖に生じたDNA一本鎖切断は非転写鎖に比較して変異および相同組換えをより高頻度で誘発する (2019)
  • Author(s): 鈴木哲矢, 紙谷浩之
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] ニックにより誘発される変異および相同組換え (2018)
  • Author(s): 鈴木 哲矢、 紙谷 浩之
  • Organizer: 第57回日本薬学会中国四国支部学術大会