Mechanisms of activation of human mRNA decapping

描述（由申请人提供）：脱帽是mRNA衰变的中心步骤。Dcp2脱盖复合物在整个真核生物中是保守的，并且是加工体（PBs）的关键组成部分，加工体是抑制信使核糖核蛋白（mRNPs）的细胞质颗粒。mRNPs被调节以允许Dcp2脱帽复合物脱帽的机制尚不清楚。这个建议的目的是获得深入了解mRNPs修改和重新准备开瓶,通过解决以下问题:1)的角色是什么c端RGG域Lsm4组件的开瓶和PB Lsm1-7复杂的形成,2)如何Dcp2开瓶复杂改造eIF4F cap-binding复杂访问信使rna帽,和3)的角色是什么mRNA的尾矿在开瓶和衰变endonucleolytically裂解mRNA吗?对这些问题的研究将为Dcp2脱壳复合物靶向mrna脱壳和衰变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见解。mRNA周转的控制对于基因表达的适当调控至关重要，其调控不当已被确定为多种人类疾病的原因或后果。本文描述的研究旨在了解人类细胞中mRNA在准备脱帽（mRNA转换的核心步骤）时被修饰和重塑的机制。这应该为mRNA调控机制提供基本的新见解，当mRNA调控解除时可能导致疾病。

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.