Amyloid-bodies and the Evolution of Malignancies

淀粉样体与恶性肿瘤的演变 项目摘要 癌细胞适应各种应激条件的能力在各种不同的 肿瘤发生的生理方面。我们最近报道了压力诱导的低复杂性的发现 来自核糖体基因间隔区(RIGSRNA)刺激物特异性位点的非编码RNA；一种神秘的 人类基因组的区域历来被认为是“垃圾”DNA。我们证明了低复杂性的rIGSRNA 激活将核仁转化为淀粉样体的生理性淀粉样蛋白：可逆核 由淀粉样蛋白固定化的蛋白质组成的无膜室。虽然许多手机 小体被描述为液状(如应激颗粒、P小体、生殖细胞颗粒)，发现 淀粉样体提供了淀粉样变性程序的证据，该程序可以在生理上转换生物学 物质变成固态。淀粉样体在正常组织的细胞亚群中发现，低密度脂蛋白的核心是 对人类肿瘤和对各种刺激作出反应的细胞进行分级，突出其无处不在的性质。蛋白质组学 分析表明，淀粉样体阻止了DNA合成机制和细胞周期的参与者 控制，在许多其他新陈代谢调节剂中。有趣的是，淀粉样体有许多共同的生物物理特征。 非洲爪哇类淀粉样固态体参与代谢抑制的特性。 同样，酵母固化其蛋白质组的成分，以在不允许的条件下形成孢子并阻止生长。 这增加了一种有趣的可能性，即受压力的癌细胞聚集淀粉样体进入孢子样结构。 极度新陈代谢抑制的状态。在这份拨款提案中，我们将展示复杂度较低的初步数据 RIGSRNA协调不寻常的RNA拖尾程序，以驱动系统范围的淀粉样蛋白形成相变。这 翻译后途径使癌细胞能够固定DNA合成机制的元件并停止 对严重环境侮辱的适应性反应中的致癌信号。基于这些初步的和 根据已发表的结果，我们假设“核仁相变程序暂时中止致癌作用”。 我们计划通过以下方式检验这一假说：1-揭示生理相变的机制；2-检验 低复杂性rIGSRNA如何激活RNA拖尾程序；3-展示RNA拖尾介导的作用 肿瘤发生中的相变。发现了驱动生理学的专用酶程序 淀粉样蛋白的发生为研究液-固相变在人类中的作用提供了一个独特的机会 临床标本和体内肿瘤检测。通过研究临床样本，在培养和原位动物模型中， 我们将测试相变是否会诱导一种独特的、但尚未确定的极端代谢的癌细胞状态 抑郁，同时强调低复杂性RNA的生化功能，通常被丢弃为无用 核酸。

Amyloid-bodies and the Evolution of Malignancies Project Summary The ability of cancer cells to adapt to a wide variety of stress conditions plays a critical role in various physiological facets of tumorigenesis. We recently reported the discovery of stress-induced low complexity noncoding RNA derived from stimuli-specific loci of the ribosomal intergenic spacer (rIGSRNA); an enigmatic region of the human genome historically dismissed as “junk” DNA. We showed that low complexity rIGSRNA activate a physiological amyloidogenic program that converts nucleoli into Amyloid-bodies: reversible nuclear membrane-less compartments composed of immobilized proteins in an amyloid-like state. While many cellular bodies have been described as liquid-like (e.g., stress granules, P-bodies, germ cell granules), the discovery of Amyloid-bodies provided evidence of an amyloidogenic program that can physiologically transition biological matter to a solid state. Amyloid-bodies are found in sub-populations of cells in normal tissues, the core of low- grade human tumors and cells responding to various stimuli highlighting their ubiquitous nature. Proteomic analysis revealed that Amyloid-bodies immobilize participants of the DNA synthesis machinery and cell cycle control, amongst many other metabolic regulators. Intriguingly, Amyloid-bodies share many biophysical properties with the amyloidogenic, solid-like Balbiani-bodies involved in metabolic suppression in Xenopus. Likewise, yeast solidify elements of their proteome to sporulate and arrest growth in non-permissive conditions. This raises the fascinating possibility that stressed cancer cells assemble Amyloid-bodies to enter a spore-like state of extreme metabolic depression. In this grant proposal, we will show preliminary data that low complexity rIGSRNA coordinate unusual RNA tailing programs to drive system-wide amyloidogenic phase transition. This post-translational pathway enables cancer cells to immobilize elements of the DNA synthesis machinery and halt oncogenic signaling in an adaptive response to severe environmental insults. Based on these preliminary and published results, we hypothesize that “Nucleolar phase transition programs temporarily suspend oncogenicity”. We plan to test this hypothesis by: 1- Uncovering mechanisms of physiological phase transition; 2- Examining how low complexity rIGSRNA activate RNA tailing programs; 3- Demonstrating a role for RNA tailing-mediated phase transition in tumorigenesis. The discovery of dedicated enzymatic programs that drive physiological amyloidogenesis provides a unique opportunity to study the role of liquid-to-solid phase transition in human clinical samples and in vivo tumor assays. By studying clinical samples, in culture and orthotopic animal models, we will test if phase transition induces a unique and yet uncharacterized cancer cell state of extreme metabolic depression, while highlighting biochemical functions for low complexity RNA typically discarded as useless nucleic acids.