Dutta Arnob, Sardiu Mihaela, Gogol Madelaine, Gilmore Joshua, Zhang Daoyong, Florens Laurence, Abmayr Susan M, Washburn Michael P, Workman Jerry L
Department of Cell and Molecular Biology, University of Rhode Island, 120 Flagg Road, Kingston, RI 02881, USA.
Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA.
Cell Rep. 2017 Feb 28;18(9):2124-2134. doi: 10.1016/j.celrep.2017.01.058.
The 12-subunit Swi/Snf chromatin remodeling complex is conserved from yeast to humans. It functions to alter nucleosome positions by either sliding nucleosomes on DNA or evicting histones. Interestingly, 20% of all human cancers carry mutations in subunits of the Swi/Snf complex. Many of these mutations cause protein instability and loss, resulting in partial Swi/Snf complexes. Although several studies have shown that histone acetylation and activator-dependent recruitment of Swi/Snf regulate its function, it is less well understood how subunits regulate stability and function of the complex. Using functional proteomic and genomic approaches, we have assembled the network architecture of yeast Swi/Snf. In addition, we find that subunits of the Swi/Snf complex regulate occupancy of the catalytic subunit Snf2, thereby modulating gene transcription. Our findings have direct bearing on how cancer-causing mutations in orthologous subunits of human Swi/Snf may lead to aberrant regulation of gene expression by this complex.
由12个亚基组成的Swi/Snf染色质重塑复合体在从酵母到人类的生物中保守存在。它通过在DNA上滑动核小体或驱逐组蛋白来改变核小体位置。有趣的是，所有人类癌症中有20%携带Swi/Snf复合体亚基的突变。其中许多突变导致蛋白质不稳定和缺失，从而产生部分Swi/Snf复合体。尽管多项研究表明组蛋白乙酰化和激活剂依赖的Swi/Snf招募调节其功能，但对于亚基如何调节复合体的稳定性和功能却了解较少。利用功能蛋白质组学和基因组学方法，我们构建了酵母Swi/Snf的网络架构。此外，我们发现Swi/Snf复合体的亚基调节催化亚基Snf2的占有率，从而调控基因转录。我们的发现直接关系到人类Swi/Snf直系同源亚基中的致癌突变如何可能导致该复合体对基因表达的异常调控。
