通过子类域对BAF复合体进行癌症特异的重定位
Gaylor Boulay1, Gabriel J Sandoval2, Nicolo Riggi3
1Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
Cell
|August 29, 2017
概括
在Ewing肉瘤中,BRG1/ BRM关联因子 (BAF) 复合体与EWSR1相互作用,由EWS- FLI1融合蛋白驱动. EWSR1的类域是招募BAF复合体进行致癌基因激活的关键.
科学领域:
- 癌症学
- 分子生物学
- 表观遗传学
背景情况:
- 转录调节器的改变导致癌症基因表达.
- 在人类瘤中,BRG1/BRM相关因子 (BAF) 染色体重塑复合物经常发生突变.
- EWSR1是一种具有类域的蛋白质,参与致癌融合.
研究的目的:
- 研究BAF复合体和EWSR1在尤宁肉瘤中的作用.
- 确定 EWS-FLI1 融合蛋白如何利用这些成分.
- 阐明致癌基因激活的机制.
主要方法:
- 染色体免疫沉以确定BAF复杂标.
- 对EWS-FLI1融合蛋白相互作用的分析.
- 对EWSR1类域氨酸残留物的突变分析.
- 使用EWSR1-FLI1融合碎片的功能研究.
主要成果:
- 在Ewing肉瘤中,BAF复合体被EWS-FLI1招募到瘤特异增强剂中.
- BAF招募导致瘤向基因激活,这是EWS-FLI1的新型功能.
- 对于复杂的BAF重定位和相位过渡来说,EWSR1类域氨酸残留是必不可少的.
- 合并到FLI1的短EWSR1片段可以回顾EWS-FLI1活动.
结论:
- EWSR1的类似子域的物理特性使BAF染色体重塑复合的重定位成为可能.
- 这种重定位对于在尤文肉瘤中建立和维持致癌基因表达程序至关重要.
- 类域可以决定癌症中染色体调节者的功能.
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