Analysis of mutagenesis relating to DNA topology, transcription and DNA repair

2020 Fiscal Year Final Research Report

• Project/Area Number: 17K00566
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Risk sciences of radiation and chemicals
• Research Institution: National Institute of Health Sciences
• Principal Investigator: Horibata Katsuyoshi 国立医薬品食品衛生研究所, 変異遺伝部, 室長 (40402995)
• Co-Investigator(Kenkyū-buntansha): 増村 健一 国立医薬品食品衛生研究所, 変異遺伝部, 室長 (40291116) ; 山田 雅巳 防衛大学校(総合教育学群、人文社会科学群、応用科学群、電気情報学群及びシステム工学群), 応用科学群, 教授 (80230481)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 転写 / 突然変異 / ＤＮＡ修復 / 遺伝毒性

Outline of Final Research Achievements

It is well known that mutagenesis is correlated positively to DNA replication, therefore, mutation(s) are rarely or hardly occurred in terminally differentiated and non-dividing silent cells e.g. neural cells in brain. However, cancer and mutations are actually induced in these silent tissues. Besides DNA replication, transcription which is the main molecular mechanism of gene expression system is the cellar function acting to DNA directly. To know the details of mutagenesis in these silent conditions, we here developed a new test system for analyzing “transcription-associated mutagenesis” in higher eukaryotes. Using this test system, we observed that highly-induced transcription by the addition of doxycycline resulted in five-times higher mutant frequency comparing to the negative control group.

Free Research Field

遺伝毒性学

Academic Significance and Societal Importance of the Research Achievements

突然変異とDNA複製には密接な正の相関関係があるとされており、これまではDNA複製の頻度が低い、あるいは細胞分裂活性が低い状態での突然変異生成についての研究は、酵母を用いたごくわずかであった。今回、"転写に関連した突然変異生成"を解析する新規実験系を確立したことで、これまで不明であった遺伝子発現過程によって生じる突然変異生成のメカニズムを解明することにつながり、さらには神経系などの細胞分裂がほとんど起きないサイレントな組織での突然変異生成や発癌過程メカニズムの解明につながる。