Characteristic mutations induced in the small intestine of Msh2-knockout gpt delta mice.

IF 2.7 4区 医学 Q2 GENETICS & HEREDITY
Yasunobu Aoki, Mizuki Ohno, Michiyo Matsumoto, Michi Matsumoto, Kenichi Masumura, Takehiko Nohmi, Teruhisa Tsuzuki
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引用次数: 1

Abstract

Background: Base pair mismatches in genomic DNA can result in mutagenesis, and consequently in tumorigenesis. To investigate how mismatch repair deficiency increases mutagenicity under oxidative stress, we examined the type and frequency of mutations arising in the mucosa of the small intestine of mice carrying a reporter gene encoding guanine phosphoribosyltransferase (gpt) and in which the Msh2 gene, which encodes a component of the mismatch repair system, was either intact (Msh2+/+::gpt/0; Msh2-bearing) or homozygously knockout (KO) (Msh2-/-::gpt/0; Msh2-KO).

Results: Gpt mutant frequency in the small intestine of Msh2-KO mice was about 10 times that in Msh2-bearing mice. Mutant frequency in the Msh2-KO mice was not further enhanced by administration of potassium bromate, an oxidative stress inducer, in the drinking water at a dose of 1.5 g/L for 28 days. Mutation analysis showed that the characteristic mutation in the small intestine of the Msh2-KO mice was G-to-A transition, irrespective of whether potassium bromate was administered. Furthermore, administration of potassium bromate induced mutations at specific sites in gpt in the Msh2-KO mice: G-to-A transition was frequently induced at two known sites of spontaneous mutation (nucleotides 110 and 115, CpG sites) and at nucleotides 92 and 113 (3'-side of 5'-GpG-3'), and these sites were confirmed to be mutation hotspots in potassium bromate-administered Msh2-KO mice. Administration of potassium bromate also induced characteristic mutations, mainly single-base deletion and insertion of an adenine residue, in sequences of three to five adenine nucleotides (A-runs) in Msh2-KO mice, and elevated the overall proportion of single-base deletions plus insertions in Msh2-KO mice.

Conclusions: Our previous study revealed that administration of potassium bromate enhanced tumorigenesis in the small intestine of Msh2-KO mice and induced G-to-A transition in the Ctnnb1 gene. Based on our present and previous observations, we propose that oxidative stress under conditions of mismatch repair deficiency accelerates the induction of single-adenine deletions at specific sites in oncogenes, which enhances tumorigenesis in a synergistic manner with G-to-A transition in other oncogenes (e.g., Ctnnb1).

Abstract Image

Abstract Image

msh2敲除gpt δ小鼠小肠中诱导的特征性突变。
背景:基因组DNA碱基对错配可导致突变,从而导致肿瘤发生。为了研究错配修复缺陷如何在氧化应激下增加致突变性,我们检查了携带编码鸟嘌呤磷酸基转移酶(gpt)的报告基因的小鼠小肠粘膜中发生突变的类型和频率,其中编码错配修复系统组成部分的Msh2基因要么是完整的(Msh2+/+::gpt/0;或纯合敲除(KO) (Msh2-/-::gpt/0;Msh2-KO)。结果:Gpt在Msh2-KO小鼠小肠中的突变频率约为msh2 -携带小鼠的10倍。在饮用水中添加1.5 g/L的氧化应激诱导剂溴酸钾28天后,Msh2-KO小鼠的突变频率没有进一步提高。突变分析表明,无论是否给予溴酸钾,Msh2-KO小鼠小肠的特征性突变都是G-to-A转变。此外,溴酸钾在Msh2-KO小鼠gpt的特定位点诱导突变:在两个已知的自发突变位点(核苷酸110和115,CpG位点)和核苷酸92和113 (5'-GpG-3'的3'侧)经常诱导G-to-A转变,这些位点被证实是溴酸钾给药的Msh2-KO小鼠的突变热点。在Msh2-KO小鼠中,溴酸钾也诱导了特征性突变,主要是3 - 5个腺嘌呤核苷酸(A-runs)序列的单碱基缺失和腺嘌呤残基插入,并提高了Msh2-KO小鼠中单碱基缺失和插入的总体比例。结论:我们之前的研究表明,施用溴酸钾可促进Msh2-KO小鼠小肠肿瘤的发生,并诱导Ctnnb1基因的G-to-A转化。基于我们目前和以前的观察,我们提出错配修复缺陷条件下的氧化应激加速了致癌基因特定位点的单腺嘌呤缺失的诱导,从而与其他致癌基因(如Ctnnb1)中的G-to-A转化协同增强了肿瘤的发生。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Genes and Environment
Genes and Environment Biochemistry, Genetics and Molecular Biology-Genetics
CiteScore
4.00
自引率
0.00%
发文量
24
审稿时长
27 weeks
期刊介绍: Genes and Environment is an open access, peer-reviewed journal that aims to accelerate communications among global scientists working in the field of genes and environment. The journal publishes articles across a broad range of topics including environmental mutagenesis and carcinogenesis, environmental genomics and epigenetics, molecular epidemiology, genetic toxicology and regulatory sciences. Topics published in the journal include, but are not limited to, mutagenesis and anti-mutagenesis in bacteria; genotoxicity in mammalian somatic cells; genotoxicity in germ cells; replication and repair; DNA damage; metabolic activation and inactivation; water and air pollution; ROS, NO and photoactivation; pharmaceuticals and anticancer agents; radiation; endocrine disrupters; indirect mutagenesis; threshold; new techniques for environmental mutagenesis studies; DNA methylation (enzymatic); structure activity relationship; chemoprevention of cancer; regulatory science. Genetic toxicology including risk evaluation for human health, validation studies on testing methods and subjects of guidelines for regulation of chemicals are also within its scope.
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