RNA metabolism mediated by the Integrator complex

Integrator 复合体介导的 RNA 代谢

• 批准号: 10447587
• 负责人: MINGYI XIE
• 金额: $ 37.53万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-13 至 2023-08-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10447587
• 关键词: Binding; Biochemical; Bruck-de Lange syndrome; Cells; Complex; Cortical Malformation; Data; Development; Disease; Enzymes; Essential Genes; Failure; Gene Expression; Generations; Genes; Growth Factor; Human; Knowledge; Malignant Neoplasms; Mediating; Messenger RNA; MicroRNAs; Molecular; Neurodegenerative Disorders; Pathologic; Process; Prostate carcinoma; Protein Subunits; RNA; RNA metabolism; RNA-Binding Proteins; Regulation; Regulator Genes; Research; Techniques; Therapeutic; Untranslated RNA; cell growth; combat; developmental disease; experience; lung Carcinoma; protein complex; response; tumor growth

PROJECT SUMMARY Project title: RNA metabolism mediated by the Integrator complex Precise recognition of RNAs by RNA-binding proteins and RNA-specific enzymes is critical for gene expression and cell growth. In recent years, the Integrator protein complex has emerged as an essential component in RNA metabolism. Disrupted RNA regulation caused by a malfunctioned Integrator has been implicated in multiple malignancies, including developmental failure (malformations of cortical development), neurodegenerative disease (Cornelia de Lange syndrome) and cancer (lung and prostate carcinomas). Yet, knowledge about the underlying pathological mechanisms is lacking. This is largely due to a limited understanding of the interplay between Integrator and its RNA substrates. We and others found that Integrator is an RNA-specific enzyme that processes several species of regulatory non-coding RNA (ncRNA). Furthermore, Integrator regulates the generation of mRNAs that are rapidly activated in response to growth factor stimulation. How Integrator recognizes RNAs through one or more of its 14 protein subunits is unclear. In the next five years, by developing new biochemical techniques, we will purify from human cells the key Integrator protein subunits that mediate RNA recognition and binding. Subsequently, we will use these RNA-recognition subunits to identify the RNAs that directly bind to, and are processed by, the Integrator complex. Our recent data suggest that one of the potential RNAs processed by Integrator are a specific set of microRNAs, small ncRNA molecules that control the function of other genes and hence are important for controlling human developmental and disease processes. microRNAs that are processed by Integrator are special in that they are produced in cells where most of the conventionally-generated microRNAs are not present. Several of these microRNAs function to suppress the growth of tumors. We will investigate how these microRNAs are uniquely generated and how they regulate the expression of other genes. There is relatively little known about the function of Integrator, how it controls RNA metabolism and how these RNAs operate within cells. Therefore, our research fills a major gap in knowledge. Our efforts in the next five years will not only uncover a new class of RNA-binding proteins as important gene regulators, but will also provide the basis for developing therapeutics to combat diseases that are caused by Integrator deficiency and dysregulated microRNAs. Techniques and experience acquired in this project will prepare our group for future research in exploring molecular machineries that generate and regulate RNAs essential for gene expression.

项目摘要 项目名称：整合子复合物介导的RNA代谢 RNA结合蛋白和RNA特异性酶对RNA的精确识别对于基因表达至关重要 和细胞生长。近年来，整合蛋白复合物已成为免疫系统中的重要组成部分。 RNA代谢。由功能障碍的整合子引起的RNA调节中断涉及 多种恶性肿瘤，包括发育障碍（皮质发育畸形）， 神经变性疾病（科尔内利亚德兰格综合征）和癌症（肺癌和前列腺癌）。然而， 缺乏关于潜在的病理机制的知识。这主要是由于有限的 了解整合剂及其RNA底物之间的相互作用。 我们和其他人发现Integrator是一种RNA特异性酶，可以处理几种不同的RNA。 调控非编码RNA（ncRNA）。此外，Integrator调节mRNA的产生， 在生长因子刺激下迅速激活。Integrator如何通过一个或多个 其14个蛋白质亚基中的更多亚基尚不清楚。在接下来的五年里，通过开发新的生化 技术，我们将从人类细胞中纯化介导RNA的关键整合蛋白亚基， 承认和约束。随后，我们将使用这些RNA识别亚基来鉴定 直接与整合子复合物结合并由其加工的RNA。 我们最近的数据表明，Integrator处理的潜在RNA之一是一组特定的 microRNA，即控制其他基因功能的小ncRNA分子，因此对 控制人类的发育和疾病过程。由Integrator加工的microRNA 特别之处在于，它们是在大多数常规产生的microRNA不存在的细胞中产生的。 礼物这些microRNA中的几种起抑制肿瘤生长的作用。我们将调查如何 这些microRNA是独特产生的，以及它们如何调节其他基因的表达。 关于Integrator的功能，它如何控制RNA代谢以及如何在细胞中表达， 这些RNA在细胞内起作用。因此，我们的研究填补了一个重大的知识空白。我们在未来的努力 五年的时间不仅会发现一类新的RNA结合蛋白作为重要的基因调节因子， 为开发治疗方法以对抗由整合剂缺乏引起的疾病提供基础， 失调的microRNAs。在这个项目中获得的技术和经验将为我们的团队将来做好准备。 研究探索产生和调节基因表达所必需的RNA的分子机制。