Action-at-a-distance mutagenesis induced by oxidized guanine in Werner syndrome protein-reduced human cells

Chemical Research in Toxicology
H KamiyaHideyoshi Harashima

Abstract

8-Oxo-7,8-dihydroguanine (G(O), 8-hydroxyguanine) in DNA is one of the most important oxidatively damaged bases and causes G:C → T:A substitution mutations. The Werner syndrome protein (WRN) is a cancer-related RecQ DNA helicase and plays many roles in DNA replication and repair. To examine the relationships between G(O)-induced mutations and WRN, shuttle plasmid DNA containing a G(O):C pair in the supF gene was transfected into human U2OS cells, in which WRN was knocked down. The plasmid DNA replicated in the knockdown cells was introduced into an Escherichia coli indicator strain. The knockdown of WRN increased the mutant frequency of the G(O)-plasmid DNA. Unexpectedly, however, the WRN knockdown only slightly enhanced the targeted G:C → T:A mutation. Instead, base-substitution mutations at various positions were more frequently detected, with statistical significance. The results obtained in this study suggested that the reduction of the cancer-related WRN induced action-at-a-distance mutagenesis by the G(O):C pair in human cells. In addition, the WRN knockdown decreased the G(O):A-induced A:T → C:G mutations, suggesting that WRN may enhance the mutations caused by G(O) in the nucleotide pool.

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Citations

Jan 1, 2015·Genes and Environment : the Official Journal of the Japanese Environmental Mutagen Society·Hiroyuki KamiyaIchiro Matsuoka
Dec 17, 2016·Genes and Environment : the Official Journal of the Japanese Environmental Mutagen Society·Tetsuya Suzuki, Hiroyuki Kamiya
Sep 29, 2020·Genes and Environment : the Official Journal of the Japanese Environmental Mutagen Society·Ruriko FukushimaHiroyuki Kamiya
Nov 23, 2019·Genes and Environment : the Official Journal of the Japanese Environmental Mutagen Society·Masanobu Kawanishi
Dec 4, 2020·Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan·Tetsuya Suzuki
Apr 5, 2018·Chemical Research in Toxicology·Tetsuya SuzukiHiroyuki Kamiya

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