Understanding mechanisms in removal of aberrant adducts from ends of genomic DNA breaks caused by radiation and other factors

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K20449
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 63020:Radiation influence-related
• Research Institution: Kyoto University
• Principal Investigator: Yamada Shintaro 京都大学, 医学研究科, 助教 (20837869)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: DNA二重鎖切断修復 / II型DNAトポイソメラーゼ

Outline of Final Research Achievements

Many genomic breaks that occur spontaneously from environmental or internal factors such as radiation are "dirty" breaks in which the cut ends are chemically modified, and are highly carcinogenic DNA damage. However, many of the molecular mechanisms of repair are unknown. In this study, we analyzed the repair mechanism of "dirty" genomic breaks by DNA topoisomerase II (Top2) as a model. Using human breast cancer cells (MCF-7) and TK6 B cells, it was found that multiple DNA repair factors including the ATM kinase are involved in the repair of "dirty" genome breaks in which Top2 is covalently bound to the ends. These results provide a basis for understanding the mechanism by which mutations accumulate in the genome due to abnormalities in the pathway that repairs "dirty" genomic breaks that occur naturally due to radiation and other factors.

Free Research Field

DNA修復

Academic Significance and Societal Importance of the Research Achievements

放射線などの環境要因や内的要因から自然発生するゲノム切断の多くは切断端が化学修飾された「汚い」切断であり、発がん性の強いDNA損傷である。この「汚 い」ゲノム切断の修復はまず切断端を「きれい」(3′末端に水酸基、5′末端にリン酸基が付いた状態)にする必要があるが、分子機構の多くが不明である。本研究では、内的要因から発生する「汚い」切断をモデルとして解析し、「汚い」ゲノム切断を「きれい」にする過程に、様々なDNA修復酵素が複合的に関わっていることを明らかにした。この成果は、放射線などにより自然発生する「汚い」ゲノム切断を修復する経路の異常により、ゲノムに変異が蓄積する機序を理解する一助となる。