Chromatin-mediated regulation of nucleolar structure and RNA Pol I localization by TOR
Chromatin-mediated regulation of nucleolar structure and RNA Pol I localization by TOR
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DOI：
10.1093/emboj/cdg578
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发表时间：
2003-11-17
期刊：
影响因子：
11.4
通讯作者：
Zheng, XFS
中科院分区：
文献类型：
--
作者：
Tsang, CK;Bertram, PG;Zheng, XFS
雷帕霉素 (TOR) 蛋白的靶点是核糖体生物合成的保守调节因子，核糖体生物合成是细胞生长和增殖的重要过程。然而，人们对 TOR 的参与方式仍知之甚少。在这项研究中，我们发现雷帕霉素和营养饥饿以及抑制 TOR 的条件会导致酵母和哺乳动物细胞的核仁尺寸显着减小。在酵母中，这种形态变化伴随着核仁中 RNA 聚合酶 I (Pol I) 的释放以及核糖体 DNA (rDNA) 转录的抑制。我们还提供了 TOR 调节 Rpd3-Sin3 组蛋白脱乙酰酶 (HDAC) 与 rDNA 染色质关联的证据，导致组蛋白 H4 的位点特异性脱乙酰化。此外，组蛋白 H4 低乙酰化突变会导致核仁大小减小和 Pol I 离域，而 rpd3Delta 和组蛋白 H4 高乙酰化突变会阻止 TOR 抑制导致的核仁变化。综上所述，我们的结果表明了一种染色质介导的机制，TOR 通过该机制调节核仁结构、RNA Pol I 定位和 rRNA 基因表达以响应营养物质的可用性。
The target of rapamycin (TOR) protein is a conserved regulator of ribosome biogenesis, an important process for cell growth and proliferation. However, how TOR is involved remains poorly understood. In this study, we find that rapamycin and nutrient starvation, conditions inhibiting TOR, lead to significant nucleolar size reduction in both yeast and mammalian cells. In yeast, this morphological change is accompanied by release of RNA polymerase I (Pol I) from the nucleolus and inhibition of ribosomal DNA (rDNA) transcription. We also present evidence that TOR regulates association of Rpd3-Sin3 histone deacetylase (HDAC) with rDNA chromatin, leading to site-specific deacetylation of histone H4. Moreover, histone H4 hypoacetylation mutations cause nucleolar size reduction and Pol I delocalization, while rpd3Delta and histone H4 hyperacetylation mutations block the nucleolar changes as a result of TOR inhibition. Taken together, our results suggest a chromatin-mediated mechanism by which TOR modulates nucleolar structure, RNA Pol I localization and rRNA gene expression in response to nutrient availability.