在BRCA1瘤抑制过程中,通过异性染色素介导的沉默发生了抑制
Quan Zhu1, Gerald M Pao, Alexis M Huynh
1Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
Nature
|September 9, 2011
概括
失去BRCA1 (乳腺癌基因1) 瘤抑制剂,通过去抑制卫星DNA,导致基因组不稳定. 通过基因素H2A无处不在,BRCA1保持了异染色质结构,这对于预防癌症至关重要.
科学领域:
- 遗传学 是一个遗传学.
- 表观遗传学 在表观遗传学中,表观遗传学是指表观遗传学.
- 癌症生物学 癌症生物学
背景情况:
- BRCA1瘤抑制基因的突变与遗传性乳腺癌和卵巢癌有关.
- 导致BRCA1损失导致瘤发生的确切机制尚未完全理解.
- 在维护基因组完整性方面,BRCA1的作用对于其瘤抑制功能至关重要.
研究的目的:
- 研究BRCA1在调节卫星DNA转录中的功能作用.
- 阐明BRCA1瘤抑制活性背后的分子机制.
- 为了确定BRCA1介导的色素维护是否与BRCA1缺陷癌症相关.
主要方法:
- 使用了 Brca1 缺乏的小鼠模型.
- 分析了连续重复的卫星DNA的转录变化.
- 在卫星重复区域评估了 histone H2A 的无处不在.
- 运用了基因素H2A-ubiquitin融合蛋白的子宫外表达.
- 在人类BRCA1缺陷乳腺癌样本中检查了卫星DNA去抑制.
主要成果:
- 在小鼠中失去Brca1导致卫星DNA的转录性去压缩.
- Brca1 缺乏导致基因组凝聚减少,并在卫星重复时失去组素 H2A 无处不在.
- BRCA1直接与卫星DNA结合,并在体内调解H2A无处不在.
- 宫外表达H2A-ubiquitin逆转了BRCA1损失的影响.
- 在人类BRCA1缺陷乳腺癌中观察到卫星DNA去抑制.
- 宫外卫星DNA表达的复制BRCA1损失效应,包括基因组不稳定性.
结论:
- 在卫星DNA重复中,BRCA1对于通过素H2A无处不在来维持异色染色质结构至关重要.
- 卫星DNA的失调有助于BRCA1缺陷癌症中观察到的基因组不稳定性.
- 在全球异染色蛋白完整性中的BRCA1的作用是其瘤抑制功能的一个关键方面.
更多相关视频
08:15gDNA Enrichment by a Transposase-based Technology for NGS Analysis of the Whole Sequence of BRCA1, BRCA2, and 9 Genes Involved in DNA Damage Repair
Published on: October 6, 2014
09:24Silencing of BRCA2 to Identify Novel BRCA2-regulated Biological Functions in Cultured Human Cells
Published on: August 12, 2015
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