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首页> 外文期刊>Journal of Molecular Biology >The Tumor Suppressor ING5 Is a Dimeric, Bivalent Recognition Molecule of the Histone H3K4me3 Mark
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The Tumor Suppressor ING5 Is a Dimeric, Bivalent Recognition Molecule of the Histone H3K4me3 Mark

机译：肿瘤抑制剂ING5是组蛋白H3K4ME3标记的二聚体，二价识别分子

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摘要

The INhibitor of Growth (ING) family of tumor suppressors regulates the transcriptional state of chromatin by recruiting remodeling complexes to sites with histone H3 trimethylated at lysine 4 (H3K4me3). This modification is recognized by the plant homeodomain (PHD) present at the C-terminus of the five ING proteins. ING5 facilitates histone H3 acetylation by the HBO1 complex, and also H4 acetylation by the MOZ/MORF complex. We show that ING5 forms homodimers through its N-terminal domain, which folds independently into an elongated coiled-coil structure. The central region of ING5, which contains the nuclear localization sequence, is flexible and disordered, but it binds dsDNA with micromolar affinity. NMR analysis of the full-length protein reveals that the two PHD fingers of the dimer are chemically equivalent and independent of the rest of the molecule, and they bind H3K4me3 in the same way as the isolated PHD. We have observed that ING5 can form heterodimers with the highly homologous ING4, and that two of three primary tumor associated mutants in the N-terminal domain strongly destabilize the coiled-coil structure. They also affect cell proliferation and cell cycle phase distribution, suggesting a driver role in cancer progression. (C) 2019 The Authors. Published by Elsevier Ltd.
机译：肿瘤抑制生长（ING）家族的抑制剂招募重塑复合在赖氨酸4（H3K4me3的）与组蛋白H3的三甲基化位点调节染色质的转录状态。本变形例是由植物同源结构域（PHD）存在于五个ING蛋白的C末端识别。 ING5促进组蛋白H3乙酰化由HBO1复杂，并且还H4乙酰由MOZ / MORF复杂。我们显示通过其N端结构域，其独立地折叠成细长的卷曲螺旋结构，其ING5形式的同型二聚体。 ING5的中心区域，其中包含核定位序列，是灵活的，无序的，但它结合双链DNA与微摩尔的亲和力。全长蛋白的NMR分析表明，该二聚体的两个手指PHD是化学上等价的并且独立于分子的其余部分，并且它们结合的H3K4me3以同样的方式作为分离的PHD。我们已观察到ING5可以形成异源二聚体与高度同源ING4，并且在N-末端结构域两个三原发性肿瘤相关突变体强烈破坏卷曲螺旋结构。他们还影响细胞增殖和细胞周期相分布，表明在癌症发展的驱动器的作用。 （c）2019年作者。 elsevier有限公司出版

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