Molecular mechanisms of action-at-a-distance mutations

2018 Fiscal Year Final Research Report

• Project/Area Number: 16H02956
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Risk sciences of radiation and chemicals
• Research Institution: Hiroshima University
• Principal Investigator: KAMIYA Hiroyuki 広島大学, 医系科学研究科(薬), 教授 (10204629)
• Co-Investigator(Kenkyū-buntansha): 鈴木 哲矢 広島大学, 医歯薬保健学研究科(薬), 助教 (20573950) ; 小松 康雄 国立研究開発法人産業技術総合研究所, 生命工学領域, 研究グループ付 (30271670)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: DNA損傷 / 遠隔作用変異

Outline of Final Research Achievements

We established a system to detect action-at-a-distance mutations (untargeted mutations found at positions apart from a DNA lesion) by incorporating the DNA lesion of interest at a downstream position of the supF gene (a reporter gene for mutations). An oxidatively damaged base, 8-hydroxyguanine, was examined using this system and found to induce the action-at-a-distance mutations (base substitution mutations in this case) frequently when the WRN protein was reduced.
We also examined another kind of DNA lesion, an abasic site. We found that it induced the action-at-a-distance mutations observed in the 8-hydroxyguanine experiments and a different type of action-at-a-distance mutations (large deletions).

Free Research Field

生物系薬学、分子生物学

Academic Significance and Societal Importance of the Research Achievements

本研究の結果、WRN蛋白質（欠損すると癌易罹患性のある早老症であるWerner症候群が発症する）が減少すると、活性酸素により生ずるDNA損傷である8-hydroxyguanineにより遠隔作用変異が誘発されることが改めて示された。また、様々な原因で生じるabasic siteにより、別種の遠隔作用変異が誘発されることも示すことができ、DNAの損傷が従来考えられてきた以上に大きな影響をもたらすことが明らかとなった。