RNA metabolism mediated by the Integrator complex

项目总结 项目标题：整合子复合体介导的RNA代谢 RNA结合蛋白和RNA特异性酶对RNA的准确识别对基因表达至关重要 和细胞生长。近年来，整合子蛋白复合体已经成为 RNA新陈代谢。因积分器故障导致的RNA调节中断已牵涉到 多种恶性肿瘤，包括发育障碍(皮质发育畸形)， 神经退行性疾病(Cornelia de Lange综合征)和癌症(肺癌和前列腺癌)。然而， 对其潜在的病理机制缺乏了解。这在很大程度上是由于 了解整合子与其RNA底物之间的相互作用。 我们和其他人发现，整合子是一种RNA专一性的酶，可以处理几种 调节性非编码RNA(NcRNA)。此外，Integrator还对符合以下条件的mRNAs的生成进行调控 对生长因子刺激的反应迅速激活。集成商如何通过一个或多个 其14个蛋白质亚基中更多的亚基尚不清楚。在未来五年，通过开发新的生物化学 技术，我们将从人类细胞中纯化介导RNA的关键整合子蛋白亚基 认可和约束。随后，我们将使用这些RNA识别亚单位来识别 直接与整合者复合体结合并由其处理的RNA。 我们最近的数据表明，由Integrator处理的潜在RNA之一是一组特定的 MicroRNAs，一种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处理的microRNAs是 特别之处在于它们是在细胞中产生的，而大多数传统上产生的microRNAs不是 现在时。这些微RNA中有几个具有抑制肿瘤生长的功能。我们将调查如何 这些微RNA是独特产生的，以及它们是如何调节其他基因的表达的。 关于整合子的功能，它是如何控制RNA新陈代谢的，以及它是如何 这些RNA在细胞内运作。因此，我们的研究填补了知识的一大空白。我们在下一步的努力 五年的时间不仅将发现一类新的RNA结合蛋白作为重要的基因调节器，而且还将 为开发治疗方法以对抗因整合者缺乏和 失调的microRNAs。在这个项目中获得的技术和经验将为我们集团的未来做好准备 探索产生和调节基因表达所必需的RNA的分子机制的研究。

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.