Specificity of DNA lesion by the DNA Polymerase zeta

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K12349
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 63030:Chemical substance influence on environment-related
• Research Institution: National Institute of Health Sciences
• Principal Investigator: Ishii Yuji 国立医薬品食品衛生研究所, 病理部, 室長 (70544881)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: DNAポリメラーゼゼータ / DNA損傷

Outline of Final Research Achievements

In this study, to elucidate the function of DNA polymerase zeta (Polζ) in response to various DNA damages, we examined the effects of reduced replication fidelity of Polzeta on gene mutations using gpt delta and Rev3l L2610M gpt delta (Rev3l) mice. These mice were treated with three renal carcinogens and kidneys were subjected to reporter gene assays. The results suggested that Polζ contributes to the extension reaction from mismatched ends caused by rubiadin-induced damage to adenine bases and to the trans-lesion synthesis (TLS) of guanine and adenine base damage. On the other hand, no differences in gene mutations induced by potassium bromate or ochratoxin A were observed between genotypes, suggesting that Polζ does not act on oxidative DNA damage or DNA double-strand breaks.

Free Research Field

化学発癌

Academic Significance and Societal Importance of the Research Achievements

これまでに明らかにしてきたベンゾ[a]ピレンが引き起こすDNA損傷に対するPolζの働きに加えて、本研究結果ではルビアジンの突然変異誘発にもPolζが寄与することが明らかとなり、Polζが様々な環境化学物質の突然変異誘発に寄与していること示唆された。一方で、酸化的DNA損傷や欠失変異の誘発には寄与していないことも明らかとなり、Polζの作用の損傷特異性について、その一端を示す情報が得られた。これらの結果はPolζの変異生成と抑制の分子機構解明の足掛かりになることが期待される。