Mechanisms and regulation of mRNA 3' processing

项目总结： 我的研究计划的长期目标是详细了解 哺乳动物mRNA3‘的加工及其调控。信使核糖核酸3‘端形成，通常 涉及内切核裂解后的聚腺苷酸化，是 真核基因的表达，并显著影响RNA代谢的许多方面， 包括信使核糖核酸的稳定性、亚细胞定位和翻译。此外，大多数人 的真核基因产生多种具有不同3‘端的mRNA异构体 交替多聚腺苷(APA)。最近的研究表明，APA具有很高的 在发育过程中受到调控，在转录后基因中发挥重要作用 监管。异常的APA模式与一系列疾病有关， 从癌症到神经性疾病。信使核糖核酸3‘中的关键悬而未决问题 加工领域包括：1)mRNA3‘的结构-功能关系是什么 加工复合体；2)信使核糖核酸3‘的加工是如何受细胞信号调节的；3)如何 受RNA结合蛋白调控的APA？我们将使用以下方法来解决这些问题 生化、结构和基因组分析。这些研究的结果不仅将 为真核基因表达的这一关键步骤提供了新的见解，但也为 为许多疾病开发新疗法的途径。

Project summary: The long-term goal of my research program is to understand, in detail, the mechanisms of mammalian mRNA 3’ processing and its regulation. mRNA 3’-end formation, typically involving an endonucleolytic cleavage followed by polyadenylation, is an essential step of eukaryotic gene expression and it significantly impacts many aspects of RNA metabolism, including mRNA stability, subcellular localization and translation. In addition, the majority of eukaryotic genes produce multiple mRNA isoforms with distinct 3’ ends through alternative polyadenylation (APA). Recent studies have revealed that APA is highly regulated in development and plays an important role in post-transcriptional gene regulation. Aberrant APA patterns have been associated with a wide range of diseases, from cancer to neurological disorders. Key outstanding questions in the mRNA 3’ processing field include: 1) what is the structure-function relationship of the mRNA 3’ processing complex; 2) how is mRNA 3’ processing regulated by cell signaling; 3) how is APA regulated by RNA-binding proteins? We will address these questions by using biochemical, structural, and genomic analyses. The results of these studies will not only provide novel insights into this key step in eukaryotic gene expression, but also pave the way for developing novel therapy for many diseases.