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。Dcp 2脱帽复合物在整个真核生物中是保守的，并且是加工体（PB）、被抑制的信使核糖核蛋白（mRNP）的细胞质颗粒的关键组分。调节mRNP以允许通过Dcp 2脱帽复合物脱帽的机制知之甚少。本提案的目的是通过解决以下问题，深入了解如何修改和改造mRNP，为开盖做准备：1）Lsm 1 -7复合物的Lsm 4组分的C末端RGG结构域在脱帽和PB形成中的作用，2）Dcp 2脱帽复合物如何重塑eIF 4F帽结合复合物以接近mRNA帽，以及3）mRNA加尾在内切核酸裂解的mRNA的去帽和衰变中的作用是什么？追求这些问题应该提供新的见解的机制，Dcp 2脱帽复合物的目标mRNA的脱帽和衰变。这将为mRNP修饰和重塑在mRNA调控中的作用提供新的基本见解。mRNA周转的控制对于基因表达的适当调节至关重要，其失调已被确定为多种人类疾病的原因或结果。本文所述的研究旨在了解人类细胞中mRNA被修饰和重塑以准备脱帽的机制，脱帽是mRNA周转的中心步骤。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.