氧化应激加速了重复序列的不稳定性和基替代,促进了MSH2缺乏小鼠的胃肠驱动突变
Mizuki Ohno1,2, Noriko Takano3,4,5, Kyoko Hidaka3,6
1Department of Medical Biophysics and Radiation Biology, Faculty of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan. mizuki.ohno.700@m.kyushu-u.ac.jp.
概括
由于MSH2缺乏而导致的DNA不匹配修复 (MMR) 损失加速了瘤的发展. 氧化应激通过促进DNA突变而加剧这种情况,增加了整体突变负担和致癌突变的可能性.
科学领域:
- 遗传学 是一个遗传学.
- 分子生物学分子生物学
- 癌症研究 癌症研究
背景情况:
- DNA不匹配修复 (MMR) 对基因组稳定性至关重要,防止DNA复制过程中的突变.
- 失去MSH2,一个关键的MMR蛋白质,导致突变和瘤发生的增加.
- 研究MSH2缺乏和氧化应激之间的相互作用对于了解癌症发展至关重要.
研究的目的:
- 研究MSH2缺乏如何与氧化应激合作,驱动突变发生和瘤发生.
- 使用rpsL记者基因测定来检测瘤发育前正常组织中的突变.
- 在MSH2缺陷模型中分析突变特征和微卫星不稳定性 (MSI).
主要方法:
- 在用氧化剂治疗的Msh2-/-小鼠中使用rpsL记者基因测定.
- 使用下一代测序进行突变特征分析.
- 进行微卫星不稳定性 (MSI) 分析.
主要成果:
- Msh2-/-小鼠的突变频率超过20倍,包括在重复性DNA序列中的基体替代和删除.
- 氧化应激显著增加了Msh2-/-小鼠的突变频率,特别是indel突变.
- Msh2-/-瘤中的突变特征与人类MMR缺乏癌症中的突变特征相似,有MSI的证据,并通过驱动突变加速了Wnt通路的激活.
结论:
- 氧化应激促进了MMR缺乏组织中的重复关联突变发生,增加了突变负担并加速了瘤发生.
- rpsL检测有效地捕获MMR缺乏和正常组织的复制不稳定性,预测瘤形成.
- 在氧化应激下,MSH2对于维持基因组稳定性至关重要,作为瘤发生的关键抑制剂.
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