Scovell William M
William M Scovell, Department of Chemistry, Bowling Green State University, Bowling Green, OH 43403, United States.
World J Biol Chem. 2016 May 26;7(2):206-22. doi: 10.4331/wjbc.v7.i2.206.
High mobility group protein 1 (HMGB1) is a multifunctional protein that interacts with DNA and chromatin to influence the regulation of transcription, DNA replication and repair and recombination. We show that HMGB1 alters the structure and stability of the canonical nucleosome (N) in a nonenzymatic, adenosine triphosphate-independent manner. As a result, the canonical nucleosome is converted to two stable, physically distinct nucleosome conformers. Although estrogen receptor (ER) does not bind to its consensus estrogen response element within a nucleosome, HMGB1 restructures the nucleosome to facilitate strong ER binding. The isolated HMGB1-restructured nucleosomes (N' and N'') remain stable and exhibit a number of characteristics that are distinctly different from the canonical nucleosome. These findings complement previous studies that showed (1) HMGB1 stimulates in vivo transcriptional activation at estrogen response elements and (2) knock down of HMGB1 expression by siRNA precipitously reduced transcriptional activation. The findings indicate that a major facet of the mechanism of HMGB1 action involves a restructuring of aspects of the nucleosome that appear to relax structural constraints within the nucleosome. The findings are extended to reveal the differences between ER and the other steroid hormone receptors. A working proposal outlines mechanisms that highlight the multiple facets that HMGB1 may utilize in restructuring the nucleosome.
高迁移率族蛋白1（HMGB1）是一种多功能蛋白，它与DNA和染色质相互作用，影响转录、DNA复制、修复及重组的调控。我们发现，HMGB1以非酶促、不依赖三磷酸腺苷的方式改变经典核小体（N）的结构和稳定性。结果，经典核小体转变为两种稳定的、物理性质不同的核小体构象体。虽然雌激素受体（ER）不与核小体内的共有雌激素反应元件结合，但HMGB1会重塑核小体以促进ER的强力结合。分离得到的HMGB1重塑核小体（N'和N''）保持稳定，并呈现出一些与经典核小体明显不同的特征。这些发现补充了先前的研究结果，即（1）HMGB1在体内刺激雌激素反应元件处的转录激活，以及（2）通过小干扰RNA敲低HMGB1表达会急剧降低转录激活。这些发现表明，HMGB1作用机制的一个主要方面涉及核小体某些方面的重塑，这似乎会放松核小体内的结构限制。这些发现进一步揭示了ER与其他类固醇激素受体之间的差异。一项可行的提议概述了一些机制，这些机制突出了HMGB1在重塑核小体时可能利用的多个方面。
