Mechanisms of human RNA turnover and quality control

项目摘要/摘要 RNA质量控制通路在清除细胞中具有缺陷的RNA方面起着至关重要的作用 由于假基因的RNA损伤、错误加工或转录而产生。很多事情都发生了 在过去的几十年中了解到了监控 蛋白质编码信使(M)RNAs，如无意义介导的mRNA衰变途径。 对监控非编码(NC)RNA的那些质量控制路径知之甚少， 它们构成了细胞≈的95%，对相同类型的损伤很敏感 MRNAs。这项研究的主要目标是揭示ncRNA 质量控制路径区分正常和缺陷的RNA，缺陷的RNA是如何 以降解为目标，这些通向细胞的途径失败的后果是什么 功能与人体健康。 为了解决这些问题，我们在未来五年将重点放在质量控制上 丰富的人类稳定的小核糖核酸，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。我们会带上 利用这些RNA的1000个假基因存在于人类基因组中的事实， 其中许多产生有缺陷的ncRNA变体，必须通过 质量控制路径。这些有缺陷的ncRNA的特征是通过质量来鉴定的 将通过以下途径揭示控制途径和涉及其退化的因素 有针对性和全局性的检测降解因子耗竭和核糖核糖核酸的效果 突变对ncRNA变异体稳定性的影响。我们最近发现了3‘的核心作用 在以有缺陷的SNRNA为目标的一种这样的质量控制路径中的末端加工机械， 因此，在未来五年内，还将进一步追求RNA目标和潜在的 RNA质量控制的3‘端加工因素，包括缺陷时引起的因素 人类神经退行性疾病。 这些努力应该揭示出有缺陷的人类小ncRNA 被质量控制路径检测和降解，这是大多数未被探索但却是关键的方面 基因表达。这些努力也有可能提供对RNA缺陷的洞察 导致人类疾病的处理，如神经退行性疾病。

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.