含有癌症相关组蛋白 H3 突变 E97K 的核小体的低温电子显微镜结构和生化分析。

IF 16.4 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Tomoaki Kimura, Seiya Hirai, Tomoya Kujirai, Risa Fujita, Mitsuo Ogasawara, Haruhiko Ehara, Shun-ichi Sekine, Yoshimasa Takizawa, Hitoshi Kurumizaka
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引用次数: 0

摘要

癌细胞中存在典型组蛋白 H3.1 Glu97 残基的 Lys 突变(H3E97K)。先前的生化分析表明,与野生型核小体相比,含有 H3E97K 突变的核小体极不稳定。然而,H3E97K 突变导致核小体不稳定的机制尚未明确。在本研究中,含有H3E97K突变的核小体的冷冻电镜结构显示,H3E97K核小体的入口/出口DNA区域紊乱,可能是由于核糖体DNA从H3 N端区域脱离。这可能会改变分子内氨基酸与被取代的 H3 Lys97 残基的相互作用,导致核小体中突变位置周围的结构扭曲。与核小体 DNA 末端的灵活性和核小体的不稳定性相一致,H3E97K 突变表现出连接组蛋白 H1 与核小体的结合减少,PRC2(表面异染色质形成所必需的甲基转移酶)与多核小体的激活缺陷,以及 RNA 聚合酶 II 的核小体转录增强。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Cryo-EM structure and biochemical analyses of the nucleosome containing the cancer-associated histone H3 mutation E97K

Cryo-EM structure and biochemical analyses of the nucleosome containing the cancer-associated histone H3 mutation E97K

The Lys mutation of the canonical histone H3.1 Glu97 residue (H3E97K) is found in cancer cells. Previous biochemical analyses revealed that the nucleosome containing the H3E97K mutation is extremely unstable as compared to the wild-type nucleosome. However, the mechanism by which the H3E97K mutation causes nucleosome instability has not been clarified yet. In the present study, the cryo-electron microscopy structure of the nucleosome containing the H3E97K mutation revealed that the entry/exit DNA regions of the H3E97K nucleosome are disordered, probably by detachment of the nucleosomal DNA from the H3 N-terminal regions. This may change the intra-molecular amino acid interactions with the replaced H3 Lys97 residue, inducing structural distortion around the mutated position in the nucleosome. Consistent with the nucleosomal DNA end flexibility and the nucleosome instability, the H3E97K mutation exhibited reduced binding of linker histone H1 to the nucleosome, defective activation of PRC2 (the essential methyltransferase for facultative heterochromatin formation) with a poly-nucleosome, and enhanced nucleosome transcription by RNA polymerase II.

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来源期刊
Accounts of Chemical Research
Accounts of Chemical Research 化学-化学综合
CiteScore
31.40
自引率
1.10%
发文量
312
审稿时长
2 months
期刊介绍: Accounts of Chemical Research presents short, concise and critical articles offering easy-to-read overviews of basic research and applications in all areas of chemistry and biochemistry. These short reviews focus on research from the author’s own laboratory and are designed to teach the reader about a research project. In addition, Accounts of Chemical Research publishes commentaries that give an informed opinion on a current research problem. Special Issues online are devoted to a single topic of unusual activity and significance. Accounts of Chemical Research replaces the traditional article abstract with an article "Conspectus." These entries synopsize the research affording the reader a closer look at the content and significance of an article. Through this provision of a more detailed description of the article contents, the Conspectus enhances the article's discoverability by search engines and the exposure for the research.
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