Mechanisms of activation of human mRNA decapping

描述(由申请人提供)：去核糖核酸是信使核糖核酸衰变的中心步骤。Dcp2解壳复合体在真核生物中是保守的，是被抑制的信使核糖核蛋白(MRNPs)的胞质颗粒加工体(PBS)的重要组成部分。MRNPs被调制为允许Dcp2解压复合体解压的机制尚不清楚。这一建议的目的是通过解决以下问题来深入了解mRNPs是如何被修饰和重塑的，以便为去包裹做准备：1)Lsm1-7复合体Lsm4组件的C-末端RGG结构域在去包裹和PB形成中起什么作用；2)Dcp2去包裹复合体如何改造eIF4F帽结合复合体以获得mRNA帽；以及3)mRNA拖尾在内切核裂解的mRNA的去掉和衰退中起什么作用？探索这些问题应该为Dcp2解离复杂的靶向mRNA进行解离和衰退的机制提供新的见解。这将为mRNP修饰和重塑在mRNA调控中的作用提供新的基础性见解。与公共卫生的相关性控制信使核糖核酸的周转对于基因表达的适当调控至关重要，而它的错误调控已被认为是多种人类疾病的原因或结果。这里描述的研究旨在了解人类细胞中的mRNAs被修饰和重塑的机制，以准备解帽，这是mRNAs周转的核心步骤。这应该为mRNA调控机制提供基本的新见解，当放松调控时，这可能会导致疾病。

DESCRIPTION (provided by applicant): Decapping is a central step in mRNA decay. The Dcp2 decapping complex is conserved throughout eukaryotes and is a key component of processing bodies (PBs), cytoplasmic granules of repressed messenger ribonucleoproteins (mRNPs). The mechanism by which mRNPs are modulated to allow decapping by the Dcp2 decapping complex is poorly understood. The objective of this proposal is to gain insights into how mRNPs are modified and remodeled in preparation for decapping, by addressing the following questions: 1) what is the role of the C-terminal RGG domain of the Lsm4 component of the Lsm1-7 complex in decapping and PB formation, 2) How does the Dcp2 decapping complex remodel the eIF4F cap-binding complex to gain access to the mRNA cap, and 3) what is the role of mRNA tailing in decapping and decay of endonucleolytically cleaved mRNA? Pursuing these questions should provide new insights into the mechanisms by which the Dcp2 decapping complex targets mRNAs for decapping and decay. This should provide new fundamental insights into the role of mRNP modification and remodeling in mRNA regulation. Relevance to Public Health The control of mRNA turnover is critical for proper regulation of gene expression, and its misregulation has been identified as a cause or a consequence of multiple human disorders. The studies described here are aimed at understanding the mechanisms by which mRNAs in human cells are modified and remodeled in preparation for decapping, a central step in mRNA turnover. This should provide fundamental new insights into mechanisms of mRNA regulation, which when deregulated can lead to disease.