一类环境和内生毒素诱导BRCA2哈普洛因不足和基因组不稳定性
Shawn Lu Wen Tan1, Saakshi Chadha1, Yansheng Liu2
1Medical Research Council Cancer Unit, University of Cambridge, Hills Road, Cambridge CB2 0XZ, UK.
Cell
|June 3, 2017
概括
环境中的毒素如甲可以通过破坏DNA复制来引发BRCA2突变患者的癌症. 这突显了普通化物对公众健康的风险.
科学领域:
- 遗传学
- 环境健康
- 分子生物学
背景情况:
- 在BRCA2瘤抑制基因突变增加癌症易感性.
- 甲是一种常见的环境毒素和细胞代谢物.
- 缺少BRCA2会损害DNA修复机制,特别是同源重组.
研究的目的:
- 为了研究甲对具有异性BRCA2突变的细胞中的DNA复制分叉的影响.
- 阐明甲影响BRCA2表达和功能的机制.
- 探索RNA-DNA杂交 (R-循环) 在化物诱导的基因组不稳定性的作用.
主要方法:
- 细胞测试以评估DNA复制叉稳定性和染色体异常.
- 蛋白体降解试验以确定BRCA2蛋白水平.
- 使用Ribonuclease H1评估R循环的作用的实验.
主要成果:
- 甲会阻断和破坏DNA复制分叉,导致BRCA2突变细胞的染色体异常.
- 甲通过蛋白体降解选择性地消耗BRCA2蛋白.
- 乙化物诱导类似的效果,而Ribonuclease H1改善了这些问题,表明R循环参与.
结论:
- 低水平的甲暴露可能会诱导BRCA2亚平素缺乏症,使携带者对癌症敏感.
- 在DNA复制过程中,可能会通过异常的R循环发生化诱导的基因组不稳定性.
- 环境和内源性化物对BRCA2突变载体构成公共健康风险.
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