Role of the DNA-unwinding enzyme Top2 in the repair of DNA double-strand breaks

2021 Fiscal Year Final Research Report

• Project/Area Number: 19H04271
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 63020:Radiation influence-related
• Research Institution: Kumamoto University
• Principal Investigator: Yano Ken-ichi 熊本大学, 産業ナノマテリアル研究所, 教授 (70311230)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: DNA損傷 / DNA修復 / DNA二重鎖切断 / DNAのねじれ / DNAトポイソメラーゼ / ライブイメージング

Outline of Final Research Achievements

DNA topoisomerase II (Top2) is an enzyme that resolves extra-winding of DNA strands and plays critical roles in various nuclear processes. A DNA double-strand break (DSB) is the most severe DNA damage caused by ionizing radiation. In the process of DSB repair, extra-winding of DNA strands can occur, but the involvement of Top2 in DSB repair is poorly understood. In this study, we analyzed dynamic behaviors of human Top2 in response to DSB induction. We found rapid accumulation of Top2 at DSB sites, its suppression by inhibitors of HDAC and PARP, altered nuclear dynamics of Top2 by Top2 inhibitors, ATP-dependent nuclear dynamics of Top2, and a novel relationship between Top2 dynamics and a certain Top2 missense mutation that causes a human hereditary disease. These new observations indicate that human Top2 participates in cellular responses to DSB induction.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

最も重篤なDNA損傷であるDSBに対して細胞にどのような応答するかについてを詳細に解明することは、人体への放射線影響を理解するために重要である。本研究では生きたヒト細胞中にDSBが生成した際にTop2の挙動がどのように変わるかについて詳細な解析を行い、ヒト細胞のDSB応答に新たな知見を加えた。またヒトの遺伝病の原因となるTop2の一アミノ酸置換の中に、Top2のDSB応答と核内動態に変化をもたらす初めての例を見いだした。