Mechanisms of human RNA turnover and quality control

项目总结/摘要 RNA质量控制途径在清除细胞中的缺陷RNA中起着重要作用， 由RNA损伤、错误加工或假基因转录引起。了很多 在过去的几十年里，我了解到质量控制的途径，监测的完整性， 蛋白质编码信使（m）RNA，如无义介导的mRNA衰变途径。 对那些监测非编码（nc）RNA的质量控制途径知之甚少， 它们占细胞RNA的95%以上，并且容易受到与 mRNA。这项研究的主要目标是揭示ncRNA在细胞内表达的机制。 质量控制途径区分正常和有缺陷的RNA， 降解的目标，以及这些途径失败的后果是什么？ 功能和人类健康。 为了解决这些问题，我们将在未来五年内专注于质量控制 丰富的人类稳定的小ncRNA，对细胞功能至关重要，包括小核 （sn）剪接体的RNA和信号识别颗粒的7SL RNA。我们将采取 利用人类基因组中存在1,000个这些RNA的假基因， 其中许多产生有缺陷的ncRNA变体，这些变体必须被检测和降解， 质量控制途径。通过质量鉴定的这些缺陷ncRNA的特征 控制途径和参与其降解的因素将通过 监测降解因子耗竭和ncRNA影响的靶向和全局测定 突变对ncRNA变体的稳定性的影响。我们最近发现了一个核心作用， 在一个这样的质量控制途径中的末端加工机制，其靶向缺陷snRNA， 因此，在接下来的五年里，我们还将继续研究RNA靶点和潜在的作用， RNA质量控制的3'端加工因素，包括当缺陷导致 人类神经退行性疾病。 这些努力应该揭示有缺陷的人类小ncRNA的原理， 通过质量控制途径检测和降解，这是一个大多未探索但关键的方面， 基因表达。这些努力也有可能为RNA缺陷提供见解 导致人类疾病如神经退行性疾病的过程。

Project Summary/Abstract RNA quality control pathways play essential roles in ridding cells of defective RNAs that arise from RNA damage, misprocessing, or transcription of pseudogenes. Much has been learned over the past decades about the quality control pathways that monitor the integrity of protein-coding messenger (m)RNAs, such as the nonsense-mediated mRNA decay pathway. Much less is known about those quality control pathways that monitor non-coding (nc)RNAs, which make up ≈95% of the cell's RNA and are susceptible to the same types of damage as mRNAs. The primary goal of this research is to uncover the mechanisms whereby ncRNA quality control pathways distinguish normal from defective RNAs, how the defective RNAs are targeted for degradation, and what are the consequence of failures in these pathways to cell function and human health. To address these questions we will over the next five years focus on the quality control of abundant human stable small ncRNAs that are critical to cell function, including small nuclear (sn)RNAs of the spliceosome and 7SL RNA of the signal recognition particle. We will take advantage of the fact that 1,000s of pseudogenes of these RNAs exist in the human genome, many of which produce defective ncRNA variants that must be detected and degraded by quality control pathways. The features of these defective ncRNAs that are identified by quality control pathways and the factors involved in their degradation will be uncovered through targeted and global assays monitoring effects of degradation factor depletion and ncRNA mutagenesis on the stability of the ncRNA variants. We recently uncovered a central role for 3' end-processing machineries in one such quality control pathway that targets defective snRNAs, and will therefore additionally over the next five years pursue RNA targets and potential roles in RNA quality control of 3' end processing factors, including factors that when defective cause human neurodegenerative disorders. These efforts should uncover principles by which defective human small ncRNAs are detected and degraded by quality control pathways, a mostly unexplored yet critical aspect of gene expression. These efforts also have the potential to provide insights into defects in RNA processing that lead to human disease such as neurodegenerative disorders.